G2Cdb::Gene report

Gene id
G00001881
Gene symbol
L1CAM (HGNC)
Species
Homo sapiens
Description
L1 cell adhesion molecule
Orthologue
G00000632 (Mus musculus)

Databases (8)

Curated Gene
OTTHUMG00000024221 (Vega human gene)
Gene
ENSG00000198910 (Ensembl human gene)
3897 (Entrez Gene)
90 (G2Cdb plasticity & disease)
L1CAM (GeneCards)
Literature
308840 (OMIM)
Marker Symbol
HGNC:6470 (HGNC)
Protein Sequence
P32004 (UniProt)

Synonyms (1)

  • CD171

Diseases (18)

Disease Nervous effect Mutations Found Literature Mutations Type Genetic association?
D00000217: X-linked hydrocephalus Y Y (1303258) Splice site mutation (SpS) Y
D00000188: Spastic paraplegia (X-linked complicated) Y Y (7562969) Unknown (?) Y
D00000176: MASA syndrome Y Y (7562969) Unknown (?) Y
D00000218: Hydrocephalus-stenosis of the aqueduct of Sylvius Y Y (7562969) Unknown (?) Y
D00000217: X-linked hydrocephalus Y Y (7762552) Unknown (?) Y
D00000176: MASA syndrome Y Y (7762552) Unknown (?) Y
D00000217: X-linked hydrocephalus Y Y (7881431) Microinsertion (MI) Y
D00000176: MASA syndrome Y Y (7881431) Microinsertion (MI) Y
D00000189: Spastic paraplegia (X-linked) Y Y (7920659) Deletion (D) Y
D00000189: Spastic paraplegia (X-linked) Y Y (7920659) Microinsertion (MI) Y
D00000176: MASA syndrome Y Y (7920659) Deletion (D) Y
D00000176: MASA syndrome Y Y (7920659) Microinsertion (MI) Y
D00000176: MASA syndrome Y Y (7920660) Deletion (D) Y
D00000176: MASA syndrome Y Y (7920660) Single nucleotide polymorphism (SNP) Y
D00000217: X-linked hydrocephalus Y Y (8069317) Splice site mutation (SpS) Y
D00000218: Hydrocephalus-stenosis of the aqueduct of Sylvius Y Y (8401593) Duplication (Du) Y
D00000217: X-linked hydrocephalus Y Y (8728703) Deletion (D) Y
D00000217: X-linked hydrocephalus Y Y (8741350) Deletion (D) Y
D00000217: X-linked hydrocephalus Y Y (8786080) Deletion (D) Y
D00000217: X-linked hydrocephalus Y Y (8929944) Frameshift mutation (FS) Y
D00000217: X-linked hydrocephalus Y Y (8929944) Nonsense (No) Y
D00000217: X-linked hydrocephalus Y Y (8929944) Microinsertion (MI) Y
D00000217: X-linked hydrocephalus Y Y (9088116) Unknown (?) Y
D00000217: X-linked hydrocephalus Y Y (9195224) Microinsertion (MI) Y
D00000217: X-linked hydrocephalus Y Y (9195224) Nonsense (No) Y
D00000217: X-linked hydrocephalus Y Y (9195224) Deletion (D) Y
D00000217: X-linked hydrocephalus Y Y (9195224) Splice site mutation (SpS) Y
D00000217: X-linked hydrocephalus Y Y (9195224) Frameshift mutation (FS) Y
D00000217: X-linked hydrocephalus Y Y (9268105) Nonsense (No) Y
D00000217: X-linked hydrocephalus Y Y (9268105) Microinsertion (MI) Y
D00000217: X-linked hydrocephalus Y Y (9268105) Deletion (D) Y
D00000217: X-linked hydrocephalus Y Y (9279760) Unknown (?) ?
D00000290: Hirschsprung's disease N Y (9279760) Unknown (?) ?
D00000217: X-linked hydrocephalus Y Y (9440802) Deletion (D) Y
D00000217: X-linked hydrocephalus Y Y (9452098) Splice site mutation (SpS) Y
D00000211: Spastic paraplegia Y Y (9452098) Splice site mutation (SpS) Y
D00000217: X-linked hydrocephalus Y Y (9521424) Splice site mutation (SpS) Y
D00000217: X-linked hydrocephalus Y Y (9521424) Microinsertion (MI) Y
D00000176: MASA syndrome Y Y (9521424) Splice site mutation (SpS) Y
D00000176: MASA syndrome Y Y (9521424) Microinsertion (MI) Y
D00000323: CRASH syndrome Y Y (9610803) Unknown (?) Y
D00000217: X-linked hydrocephalus Y Y (9643285) Single nucleotide polymorphism (SNP) Y
D00000218: Hydrocephalus-stenosis of the aqueduct of Sylvius Y Y (9744477) Microinsertion (MI) Y
D00000218: Hydrocephalus-stenosis of the aqueduct of Sylvius Y Y (9744477) Nonsense (No) Y
D00000218: Hydrocephalus-stenosis of the aqueduct of Sylvius Y Y (9744477) Deletion (D) Y
D00000218: Hydrocephalus-stenosis of the aqueduct of Sylvius Y Y (9744477) Splice site mutation (SpS) Y
D00000176: MASA syndrome Y Y (9744477) Microinsertion (MI) Y
D00000176: MASA syndrome Y Y (9744477) Nonsense (No) Y
D00000176: MASA syndrome Y Y (9744477) Deletion (D) Y
D00000176: MASA syndrome Y Y (9744477) Splice site mutation (SpS) Y
D00000217: X-linked hydrocephalus Y Y (10797421) Nonsense (No) Y
D00000217: X-linked hydrocephalus Y Y (10797421) Frameshift mutation (FS) Y
D00000217: X-linked hydrocephalus Y Y (10797421) Splice site mutation (SpS) Y
D00000166: Schizophrenia Y Y (11425011) Single nucleotide polymorphism (SNP) Y
D00000215: Hydrocephalus Y Y (11857550) Single nucleotide polymorphism (SNP) ?
D00000290: Hirschsprung's disease N Y (11857550) Single nucleotide polymorphism (SNP) ?
D00000217: X-linked hydrocephalus Y Y (12435569) Microinsertion (MI) Y
D00000217: X-linked hydrocephalus Y Y (12725590) Unknown (?) Y
D00000217: X-linked hydrocephalus Y Y (15108295) Single nucleotide polymorphism (SNP) Y
D00000217: X-linked hydrocephalus Y Y (15108295) Deletion (D) Y
D00000217: X-linked hydrocephalus Y Y (15108295) Insertion (I) Y
D00000217: X-linked hydrocephalus Y Y (15148591) Splice site mutation (SpS) Y
D00000217: X-linked hydrocephalus Y Y (15148591) Nonsense (No) Y
D00000290: Hirschsprung's disease N Y (15148591) Splice site mutation (SpS) Y
D00000290: Hirschsprung's disease N Y (15148591) Nonsense (No) Y
D00000216: L1 syndrome Y Y (15662685) Unknown (?) Y
D00000216: L1 syndrome Y Y (15904436) Nonsense (No) Y
D00000216: L1 syndrome Y Y (16088863) Deletion (D) Y
D00000216: L1 syndrome Y Y (16650080) Microinsertion (MI) Y
D00000216: L1 syndrome Y Y (16816908) Microinsertion (MI) Y
D00000215: Hydrocephalus Y Y (17294222) Deletion (D) Y
D00000292: Duplex kidneys N Y (17294222) Deletion (D) Y
D00000218: Hydrocephalus-stenosis of the aqueduct of Sylvius Y Y (17318848) Microdeletion (MD) Y
D00000271: Nephrogenic diabetes insipidus N Y (17318848) Microdeletion (MD) Y
D00000216: L1 syndrome Y Y (17328266) Nonsense (No) Y
D00000216: L1 syndrome Y Y (17328266) Frameshift mutation (FS) Y
D00000216: L1 syndrome Y Y (17328266) Splice site mutation (SpS) Y
D00000198: Epilepsy (autosomal dominant partial with auditory features) Y Y (15079010) Microinsertion (MI) Y
D00000198: Epilepsy (autosomal dominant partial with auditory features) Y Y (15079011) Microinsertion (MI) Y
D00000202: Epilepsy (temporal lobe) Y Y (15199738) No mutation found (N) N
D00000207: Hereditary motor and sensory neuropathy Y Y (15199738) No mutation found (N) N
D00000201: Epilepsy (partial with auditory features) Y Y (15654555) No mutation found (N) N
D00000197: Epilepsy (autosomal dominant lateral temporal) Y Y (17296837) Single nucleotide polymorphism (SNP) Y
D00000197: Epilepsy (autosomal dominant lateral temporal) Y Y (17296837) Single nucleotide polymorphism (SNP) Y

References

  • L1CAM mutation in a boy with hydrocephalus and duplex kidneys.

    Liebau MC, Gal A, Superti-Furga A, Omran H and Pohl M

    Department of Pediatrics and Adolescent Medicine, University Hospital of Freiburg, Mathildenstrasse 1, 79106, Freiburg, Germany.

    Mutations in the X-chromosomal gene (L1CAM) for cell adhesion molecule L1 are associated with a heterogeneous group of conditions that include agenesis of the corpus callosum, hydrocephalus, spastic paraplegia, adducted thumbs and mental retardation (L1-spectrum disease, CRASH or MASA syndrome). Although L1CAM is expressed during renal development and L1cam-deficient mice have congenital malformations of the kidney and the urinary tract, L1CAM mutations have not been associated with renal anomalies in men. We report on a boy with prenatally detected hydrocephalus. After his birth, bilateral duplex kidneys and ureters, with a unilateral mega-ureter serving a hydronephrotic upper pole, as well as agenesis of the corpus callosum, adducted thumbs, spasticity, and mental retardation were recognized, fulfilling the criteria of an L1-spectrum disease. Genetic testing of the patient and his mother identified a 2 bp deletion in the invariant splice consensus sequence of intron 18 of L1CAM, predicting a largely truncated or absent protein. At the age of 9 years, 7 years after heminephrectomy, the boy has normal renal function. This observation suggests that patients with L1CAM mutations may have renal abnormalities as seen in the L1cam-deficient mouse model. L1CAM might, therefore, also be considered a possible candidate gene for renal malformations.

    Pediatric nephrology (Berlin, Germany) 2007;22;7;1058-61

  • Contiguous gene deletion involving L1CAM and AVPR2 causes X-linked hydrocephalus with nephrogenic diabetes insipidus.

    Tegay DH, Lane AH, Roohi J and Hatchwell E

    Stony Brook University Hospital, Stony Brook, New York, USA. david.tegay@stonybrook.edu

    X-linked hydrocephalus with aqueductal stenosis (HSAS) is caused by mutation or deletion of the L1 cell adhesion molecule gene (L1CAM) at Xq28. Central diabetes insipidus (CDI) can arise as a consequence of resultant hypothalamic dysfunction from hydrocephalus and must be distinguished from nephrogenic diabetes insipidus (NDI) by exogenous vasopressin response. Causes of NDI are heterogeneous and include mutation or deletion of the arginine vasopressin receptor 2 gene (AVPR2), which is located approximately 29 kb telomeric to L1CAM. We identified a patient with both HSAS and NDI where DNA sequencing failure suggested the possibility of a contiguous gene deletion. A 32.7 kb deletion mapping from L1CAM intron1 to AVPR2 exon2 was confirmed. A 90 bp junctional insertion fragment sharing short direct repeat homology with flanking sequences was identified. To our knowledge this is the first reported case of an Xq28 microdeletion involving both L1CAM and AVPR2, defining a new contiguous gene syndrome comprised of HSAS and NDI. Contiguous gene deletion should be considered as a mechanism for all patients presenting with hydrocephalus and NDI.

    Funded by: NIGMS NIH HHS: T32 GM008444

    American journal of medical genetics. Part A 2007;143A;6;594-8

  • Two novel epilepsy-linked mutations leading to a loss of function of LGI1.

    Chabrol E, Popescu C, Gourfinkel-An I, Trouillard O, Depienne C, Senechal K, Baulac M, LeGuern E and Baulac S

    INSERM UMR 679, Neurologie and Thérapeutique Expérimentale, Université Pierre et Marie Curie-Paris 6, Faculté de Médecine, Assistance Publique-Hôpitaux de Paris, Hôpital de la Pitié-Salpêtrière, 47 boulevard de l'hôpital, 75013 Paris, France.

    Background: Mutations in the leucine-rich, glioma-inactivated 1 (LGI1) gene have been implicated in autosomal dominant lateral temporal epilepsy.

    Objective: To describe the clinical and genetic findings in 2 families with autosomal dominant lateral temporal epilepsy and the functional consequences of 2 novel mutations in LGI1.

    Design: Clinical, genetic, and functional investigations.

    Setting: University hospital. Patients Two French families with autosomal dominant lateral temporal epilepsy. Main Outcome Measure Mutation analysis.

    Results: Two novel disease-linked mutations, p.Leu232Pro and c.431 + 1G>A, were identified in LGI1. We demonstrated that the c.431 + 1G>A mutation causes the deletion of exons 3 and 4 of the LGI1 transcript and showed that the p.Leu232Pro mutation dramatically decreases secretion of the mutant protein by mammalian cells.

    Conclusion: Our data indicate that LGI1 is a secreted protein and suggest that LGI1-related epilepsy results from a loss of function.

    Archives of neurology 2007;64;2;217-22

  • Molecular mechanisms and neuroimaging criteria for severe L1 syndrome with X-linked hydrocephalus.

    Kanemura Y, Okamoto N, Sakamoto H, Shofuda T, Kamiguchi H and Yamasaki M

    Institute for Clinical Research and Department of Neurosurgery, Osaka National Hospital, Osaka, Japan.

    Object: Mutations in the gene that codes for the human neural cell adhesion molecule L1 (L1CAM), are known to cause a wide variety of anomalies, now understood as phenotypic expressions of L1 syndrome. The correlations between genotype and phenotype, however, are not fully established. The authors report the results of a nationwide investigation of L1CAM gene mutations that was performed to improve the understanding of L1-mediated molecular mechanisms of X-linked hydrocephalus and to establish neurorimaging criteria for this severe form of L1 syndrome.

    Methods: Ninety-six genomic DNA samples from members of 57 families were obtained from the Congenital Hydrocephalus Research Committee. By using polymerase chain reaction and direct DNA sequencing, the authors identified 25 different L1CAM gene mutations, 20 of them novel, in 26 families with X-linked hydrocephalus. All the mutations were L1CAM loss-of-function mutations, and all the patients had severe hydrocephalus and severe mental retardation. In all cases, specific abnormalities were visible on neuroimaging: a rippled ventricular wall after shunt placement, an enlarged quadrigeminal plate, a large massa intermedia, and hypoplasia of the cerebellar vermis (anterior or total). The patients also had adducted thumbs, spastic paraplegia, and hypoplasia of the corpus callosum, which are characteristic of L1 syndrome.

    Conclusions: The L1CAM loss-of-function mutations cause a severe form of L1 syndrome, unlike the milder form produced by mutations in the L1CAM cytoplasmic domain. We also identified neurorimaging criteria for this severe form of L1 syndrome. These criteria can be used to predict loss-of-function mutations in patients with X-linked hydrocephalus and to help in diagnosing this syndrome.

    Journal of neurosurgery 2006;105;5 Suppl;403-12

  • A novel missense mutation in the L1CAM gene in a boy with L1 disease.

    Simonati A, Boaretto F, Vettori A, Dabrilli P, Criscuolo L, Rizzuto N and Mostacciuolo ML

    Department of Neurological and Visual Science, Section of Clinical Neurology-Child Neurology Unit, Policlinico G. B. Rossi, Verona, and Department of Biology, Laboratory of Human Genetics, University of Pauda, Italy. alessandro.simonati@univr.it

    A novel missense mutation of the L1CAM gene (Xq28) is described in an adult patient affected with severe mental retardation, spastic paraparesis, adducted thumbs, agenesis of corpus callosum and microcephaly (L1 disease). We detected a transition c2308G-->A in exon 18 that caused an amino acid change in codon 770. The patient's mother and two sisters were heterozygous for the same mutation. This newly described mutation predicts the substitution of an aspartate by asparagine (D770N) in the second fibronectin (Fn2) domain of the extracellular portion of the mature L1 protein. Even if amino acid substitution does not significantly change the physico-chemical properties of the Fn2 domain, it seems clear that the integrity of this domain is required to maintain the biological functions of the protein. The feature peculiar to this patient is the decelerated head growth post-natally, leading to microcephaly. Mutations of L1CAM associated with prolonged survival may hamper post-natal brain and head growth.

    Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology 2006;27;2;114-7

  • Expanding the phenotypic spectrum of L1CAM-associated disease.

    Basel-Vanagaite L, Straussberg R, Friez MJ, Inbar D, Korenreich L, Shohat M and Schwartz CE

    Department of Medical Genetics, Rabin Medical Center, Beilinson Campus, Petah Tikva, Israel. basel@post.tau.ac.il

    Mutations in the L1CAM gene cause neurological abnormalities of variable severity, including congenital hydrocephalus, agenesis of the corpus callosum, spastic paraplegia, bilaterally adducted thumbs, aphasia, and mental retardation. Inter- and intrafamilial variability is a well-known feature of the L1CAM spectrum, and several patients have a combination of L1CAM mutations and Hirschsprung's disease (HSCR). We report on two siblings with a missense mutation in exon 7 (p.P240L) of the L1CAM gene. In one of the siblings, congenital dislocation of the radial heads and HSCR were present. Neither patient had hydrocephalus, adducted thumbs, or absent speech, but both had a hypoplastic corpus callosum. We suggest that L1CAM mutation testing should be considered in male patients with a positive family history compatible with X-linked inheritance and either the combination of agenesis of the CC and HSCR or the combination of agenesis of the CC and limb abnormalities, including abnormalities other than adducted thumbs.

    Funded by: NICHD NIH HHS: HD26202

    Clinical genetics 2006;69;5;414-9

  • Prenatal diagnosis in a family with X-linked hydrocephalus.

    Panayi M, Gokhale D, Mansour S and Elles R

    National Genetics Reference Laboratory, Regional Genetics Service, St Mary's Hospital, Manchester, UK. maria.panayi@cmmc.nhs.uk

    The neural cell adhesion molecule L1 is a transmembrane glycoprotein belonging to the immunoglobulin superfamily of cell adhesion molecules (CAMs). Its expression is essential during embryonic development of the nervous system and it is involved in cognitive function and memory. Mutations in the L1CAM gene are responsible for four related L1 disorders; X-linked hydrocephalus/HSAS (Hydrocephalus as a result of Stenosis of the Aqueduct of Sylvius), MASA (Mental retardation, Aphasia, Shuffling gait, and Adducted thumbs) syndrome, X-linked complicated spastic paraplegia type I (SPG1) and X-linked Agenesis of the Corpus Callosum (ACC). These four disorders represent a clinical spectrum that varies both between and within families. The main clinical features of this spectrum are Corpus callosum hypoplasia, mental Retardation, Adducted thumbs, Spastic paraplegia and Hydrocephalus (CRASH syndrome). Since there is no biochemically assayed disease marker, molecular analysis of the L1CAM gene is the only means of confirming a clinical diagnosis. Most L1CAM mutations reported to date are point mutations (missense, nonsense, splice site) and only a few patients with larger rearrangements have been documented. We have characterised a rare intragenic deletion of the L1CAM gene in a sample of DNA extracted from a chorionic villus biopsy (CVB) performed at 12 weeks' gestation. =

    Prenatal diagnosis 2005;25;10;930-3

  • First case of L1CAM gene mutation identified in MASA syndrome in Asia.

    Kanemura Y, Takuma Y, Kamiguchi H and Yamasaki M

    Institute for Clinical Research, Osaka National Hospital, National Hospital Organization, Osaka 540-0006, Japan.

    We report here the first case of an L1CAM gene mutation identified in mental retardation, adducted thumbs, shuffling gait, and aphasia (MASA) syndrome in Japan. The patient was a 10-year-old boy with mild mental retardation, bilateral adducted thumbs and corpus callosum hypoplasia. His family had no history of MASA syndrome. The L1CAM gene contained a nonsense mutation (R1166X) in exon 26 in the cytoplasmic domain. No mutation was found in the extracellular and transmembrane domains of L1CAM. The abnormal development of axon tracts resulting in the corpus callosum hypoplasia and adducted thumbs appears to be caused by malfunction of the cytoplasmic domain of L1CAM.

    Congenital anomalies 2005;45;2;67-9

  • A novel L1CAM mutation with L1 spectrum disorders.

    Silan F, Ozdemir I and Lissens W

    Medical Biology and Genetic Department, Abant Izzet Baysal University, Duzce School of Medicine, Duzce, Turkey. fsilan@yahoo.com

    X-linked hydrocephalus, HSAS (hydrocephalus due to stenosis of aqueduct of Sylvius), MASA (mental retardation, aphasia, shuffling gait, and adducted thumbs), and CRASH (corpus callosum hypoplasia, retardation, adducted thumbs, spastic paraplegia, and hydrocephalus) syndromes are allelic disorders. X-linked hydrocephalus and associated phenotypes are due to mutations in the L1CAM gene, which has been identified as a coding neural cell adhesion molecule. We report two cases of L1 spectrum disorders within the same family. The first case was diagnosed by ultrasonographic examination prenatally and the second case was diagnosed postnatally. Both patients and their mothers carry a novel mutation of the L1CAM gene. In this family, nine X-linked hydrocephalus and five female carriers were found in three generations, and molecular genetic analysis was performed to detect the asymptomatic carriers.

    Prenatal diagnosis 2005;25;1;57-9

  • LGI1 gene mutation screening in sporadic partial epilepsy with auditory features.

    Flex E, Pizzuti A, Di Bonaventura C, Douzgou S, Egeo G, Fattouch J, Manfredi M, Dallapiccola B and Giallonardo AT

    Dipartimento di Medicina Sperimentale e Patologia, Universita' di Roma La Sapienza, Rome, Italy.

    Partial epilepsy with auditory features occasionally segregates in families as an autosomal dominant trait. In some families mutations in the leucine-rich glioma inactivated (LGI1) gene have been identified. Sporadic cases might harbour either denovo or low-penetrant LGI1 mutations, which will substantially alter the family risk for epilepsy. We selected sixteen sporadic patients with cryptogenic temporal lobe epilepsy and partial seizures with auditory features. We compared clinical features of these patients with those of published autosomal dominant family cases. We screened these patients for LGI1 mutations. Comparing the sporadic patients with the published familial cases no difference in either the primary auditory features or in the other associated epileptic manifestations was identified. Sequence analysis of the whole LGI1 gene coding regions in sporadic patients did not reveal changes in the LGI1 gene. The genetic analysis demonstrates that LGI1 is not a major gene for sporadic cases of partial epilepsy with auditory features at least in the Italian population. Screening of sporadic patients for LGI1 mutations appears not useful in genetic counselling of these patients.

    Journal of neurology 2005;252;1;62-6

  • Intronic mutations in the L1CAM gene may cause X-linked hydrocephalus by aberrant splicing.

    Hübner CA, Utermann B, Tinschert S, Krüger G, Ressler B, Steglich C, Schinzel A and Gal A

    Institute of Human Genetics, University Hospital Eppendorf, Hamburg, Germany. c.huebner@uke.uni-hamburg.de

    L1 disease is a clinically heterogeneous X-chromosomal neurodevelopmental disorder that is frequently associated with mental retardation and congenital hydrocephalus in males. It is caused by mutations in L1CAM that encodes a multifunctional transmembrane neuronal cell adhesion molecule. We report our findings on 6 novel intronic L1CAM sequence variants (c.523+5G>A, c.1123+1G>A, c.1547-13delC, c.3323-17dupG, c.3457+3A>T, and c.3457+18C>T), and a recurrent one (c.523+12C>T). While the pathogenic potential of nucleotide changes within the evolutionarily well-conserved splice consensus sequence (c.523+5G>A, c.1123+1G>A, and c.3457+3A>T) is widely accepted, it is not always straight forward to assess the disease relevance of intronic mutations, if they lie outside the consensus. The c.523+12C>T variant co-segregated with X-linked hydrocephalus in two unrelated families. In the mutated allele, a preferentially used novel splice donor site is generated that results in a frame shift due to insertion of the first 10 bp of intron 5 in the mature mRNA, a largely truncated protein, and most likely a functional null allele. The c.1547-13delC mutation creates a new acceptor site resulting in the insertion of 4 additional amino acids at the end of the immunoglobulin like domain 5. In contrast, c.3323-17dupG and c.3457+18C>T seem to be non-pathogenic L1CAM variants.

    Human mutation 2004;23;5;526

  • LGI1 mutations in autosomal dominant partial epilepsy with auditory features.

    Ottman R, Winawer MR, Kalachikov S, Barker-Cummings C, Gilliam TC, Pedley TA and Hauser WA

    Gertrude H. Sergievsky Center, Columbia University, New York, NY 10032, USA. ro6@columbia.edu

    Objective: S: Mutations in LGI1 cause autosomal dominant partial epilepsy with auditory features (ADPEAF), a form of familial temporal lobe epilepsy with auditory ictal manifestations. The authors aimed to determine what proportion of ADPEAF families carries a mutation, to estimate the penetrance of identified mutations, and to identify clinical features that distinguish families with and without mutations.

    Methods: The authors sequenced LGI1 in 10 newly described ADPEAF families and analyzed clinical features in these families and others with mutations reported previously.

    Results: Three of the families had missense mutations in LGI1 (C42R, I298T, and A110D). Penetrance was 54% in eight families with LGI1 mutations the authors have identified so far (five reported previously and three reported here). Excluding the original linkage family, the authors have found mutations in 50% (7/14) of tested families. Families with and without mutations had similar clinical features, but those with mutations contained significantly more subjects with auditory symptoms and significantly fewer with autonomic symptoms. In families with mutations, the most common auditory symptom type was simple, unformed sounds (e.g., buzzing and ringing). In two of the newly identified families with mutations, some subjects with mutations had idiopathic generalized epilepsies.

    Conclusions: LGI1 mutations are a common cause of autosomal dominant partial epilepsy with auditory features. Current data do not reveal a clinical feature that clearly predicts which families with autosomal dominant partial epilepsy with auditory features have a mutation. Some families with LGI1 mutations contain individuals with idiopathic generalized epilepsies. This could result from either an effect of LGI1 on risk for generalized epilepsy or an effect of co-occurring idiopathic generalized epilepsy-specific genes in these families.

    Funded by: NINDS NIH HHS: R01 NS020656, R01 NS036319, R01 NS036319-08, R01 NS043472, R01 NS043472-05, R01 NS36319

    Neurology 2004;62;7;1120-6

  • LGI1 mutations in temporal lobe epilepsies.

    Berkovic SF, Izzillo P, McMahon JM, Harkin LA, McIntosh AM, Phillips HA, Briellmann RS, Wallace RH, Mazarib A, Neufeld MY, Korczyn AD, Scheffer IE and Mulley JC

    Epilepsy Research Institute and Department of Medicine, University of Melbourne, Victoria, Australia. s.berkovic@unimelb.edu.au

    A number of familial temporal lobe epilepsies (TLE) have been recently recognized. Mutations in LGI1 (leucine-rich, glioma-inactivated 1 gene) have been found in a few families with the syndrome of autosomal dominant partial epilepsy with auditory features (ADPEAF). The authors aimed to determine the spectrum of TLE phenotypes with LGI1 mutations, to study the frequency of mutations in ADPEAF, and to examine the role of LGI1 paralogs in ADPEAF without LGI1 mutations.

    Methods: The authors performed a clinical and molecular analysis on 75 pedigrees comprising 54 with a variety of familial epilepsies associated with TLE and 21 sporadic TLE cases. All were studied for mutations in LGI1. ADPEAF families negative for LGI1 mutations were screened for mutations in LGI2, LGI3, and LGI4.

    Results: Four families had ADPEAF, 22 had mesial TLE, 11 had TLE with febrile seizures, two had TLE with developmental abnormalities, and 15 had various other TLE syndromes. LGI1 mutations were found in two of four ADPEAF families, but in none of the other 50 families nor in the 21 individuals with sporadic TLE. The mutations were novel missense mutations in exons 1 (c.124T-->G; C42G) and 8 (c.1418C-->T; S473L). No mutations in LGI2, LGI3, or LGI4 were found in the other two ADPEAF families.

    Conclusion: In TLE, mutations in LGI1 are specific for ADPEAF but do not occur in all families. ADPEAF is genetically heterogeneous, but mutations in LGI2, LGI3, or LGI4 did not account for families without LGI1 mutations.

    Neurology 2004;62;7;1115-9

  • [A family with autosomal dominant temporal lobe epilepsy accompanied by motor and sensory neuropathy].

    Matsuoka T, Furuya H, Ikezoe K, Murai H, Ohyagi Y, Yoshiura T, Sasaki M, Tobimatsu S and Kira J

    Department of Neurology, Graduate School of Medical Sciences, Kyushu University.

    We report a 20-year-old man with temporal lobe epilepsy (TLE) accompanied by hereditary motor and sensory neuropathy (HMSN). He had experienced complex partial seizures (CPS), which started with a nausea-like feeling, followed by loss of consciousness and automatism, since he was 6 years old. The frequency of attacks was at first decreased by phenytoin. However, attacks increased again when he was 18 years old. On admission, neurological examination showed mild weakness of the toes, pes cavus, hammer toe and mildly impaired vibratory sensation in his legs. Ten people in four generations of his family showed a history of epilepsy in the autosomal dominant inheritance form. His younger sister and mother had a history of epilepsy accompanied with pes cavus, hammer toe, weakness of toe and finger extension and mildly impaired vibratory sensation as well. Direct sequencing of the glioma-inactivated leucine-rich gene (LGI1), in which several mutations were reported in patients with familial lateral temporal lobe epilepsy, showed no specific mutation in this family. On consecutive video-EEG monitoring, paroxysmal rhythmic activity was confirmed in his left fronto-temporal region when he showed automatism, and then a generalized slow burst activity was detected when he lost consciousness. For his seizures, TLE with secondary generalization was diagnosed. In the nerve conduction study, delayed nerve conduction, distal motor latency and decreased amplitudes of the compound muscle action potentials (CMAP) of bilateral peroneal nerves were observed, indicating the existence of mild axonal degeneration. Based on these data, we consider that this family to be a new phenotype of autosomal dominant TLE accompanied by motor and sensory neuropathy.

    Rinsho shinkeigaku = Clinical neurology 2004;44;1;43-9

  • Hydrocephalus and Hirschsprung's disease with a mutation of L1CAM.

    Okamoto N, Del Maestro R, Valero R, Monros E, Poo P, Kanemura Y and Yamasaki M

    Department of Planning and Research, Osaka Medical Center and Research Institute for Maternal and Child Health, 840 Murodo-cho, Izumi, Osaka 594-1101, Japan. okamoto@osaka.email.ne.jp

    Abnormalities of the L1CAM gene, a member of the immunoglobulin gene superfamily of neural-cell adhesion molecules, are associated with X-linked hydrocephalus and some allelic disorders. Hirschsprung's disease (HSCR) is characterized by the absence of ganglion cells and the presence of hypertrophic nerve trunks in the distal bowel. There have been three reports of patients with X-linked hydrocephalus and HSCR with a mutation in the L1CAM gene. We report three more patients with similar conditions. We suspect that decreased L1CAM may be a modifying factor in the development of HSCR.

    Journal of human genetics 2004;49;6;334-7

  • X-linked hydrocephalus: another two families with an L1 mutation.

    Rodríguez Criado G, Pérez Aytés A, Martínez F, Vos YJ, Verlind E, González-Meneses López A, Gómez de Terreros Sánchez I and Schrander-Stumpel C

    Unidad de Dismorfología, H.I.U.V. Rocío, Sevilla, Spain.

    X-linked hydrocephalus is a variable condition caused by mutations in the gene encoding for L1CAM. This gene is located at Xq28. Clinically the spectrum ranges from males with lethal congenital hydrocephalus to mild/moderate mental retardation and spastic paraplegia. Few carrier females show minimal signs of the syndrome. Although most cases are familial, de novo situations have been reported. We report two new families with the syndrome and a L1 mutation. Family 1 has two patients and family 2 a single patient. Clinical diagnosis in all three affected boys was beyond doubt. Prenatal testing through chorionic villus biopsy is possible only with a demonstrated L1 mutation. In lethal sporadic cases neuropathology is very important in order to evaluate for features of the syndrome. We stress the importance of further clinical reports including data on neuropathology and DNA analysis in order to further understand the mechanisms involved in this disorder.

    Genetic counseling (Geneva, Switzerland) 2003;14;1;57-65

  • X-linked hydrocephalus: a novel missense mutation in the L1CAM gene.

    Sztriha L, Vos YJ, Verlind E, Johansen J and Berg B

    Department of Pediatrics, Faculty of Medicine and Health Sciences, United Arab Emirates University, Al Ain.

    X-linked hydrocephalus is associated with mutations in the L1 neuronal cell adhesion molecule gene. L1 protein plays a key role in neurite outgrowth, axonal guidance, and pathfinding during the development of the nervous system. A male is described with X-linked hydrocephalus who had multiple small gyri, hypoplasia of the white matter, agenesis of the corpus callosum, and lack of cleavage of the thalami. Scanning the L1 neuronal cell adhesion molecule gene in Xq28 revealed a novel missense mutation: transition of a guanine to cytosine at position 1,243, which led to conversion of alanine to proline at position 415 in the Ig 4 domain of the L1 protein. It is likely that the X-linked hydrocephalus and cerebral dysgenesis are a result of the abnormal structure and function of the mutant L1 protein.

    Pediatric neurology 2002;27;4;293-6

  • Hydrocephalus and intestinal aganglionosis: is L1CAM a modifier gene in Hirschsprung disease?

    Parisi MA, Kapur RP, Neilson I, Hofstra RM, Holloway LW, Michaelis RC and Leppig KA

    Division of Genetics and Development, Department of Pediatrics, University of Washington and Children's Hospital and Regional Medical Center, Seattle, Washington 98105, USA. mparisi@u.washington.edu

    Congenital hydrocephalus associated with aqueductal stenosis and/or agenesis of the corpus callosum has been described in newborn males with mutations in L1CAM, a gene that encodes a neural cell adhesion molecule. These males usually have severe mental retardation and may have spastic paraplegia and adducted thumbs. In contrast, Hirschsprung disease, or absence of ganglion cells in the distal gut, has rarely been described in such individuals. We report a male infant who had severe hydrocephalus identified in the prenatal period with evidence of aqueductal stenosis and adducted thumbs at birth. He developed chronic constipation, and rectal biopsy confirmed the diagnosis of Hirschsprung disease. Molecular testing of the L1CAM gene revealed a G2254A mutation, resulting in a V752M amino acid substitution. A common polymorphism in RET, but no mutation, was identified. Our patient represents the third example of coincident hydrocephalus and Hirschsprung disease in an individual with an identified L1CAM mutation. We hypothesize that L1CAM-mediated cell adhesion may be important for the ability of ganglion cell precursors to populate the gut, and that L1CAM may modify the effects of a Hirschsprung disease-associated gene to cause intestinal aganglionosis.

    Funded by: NICHD NIH HHS: P30-HD28834; NIDDK NIH HHS: R01-DK52530

    American journal of medical genetics 2002;108;1;51-6

  • An association study between polymorphism of L1CAM gene and schizophrenia in a Japanese sample.

    Kurumaji A, Nomoto H, Okano T and Toru M

    Department of Neuropsychiatry, Tokyo Medical and Dental University School of Medicine, Japan. 0724.psyc@med.tmd.ac.jp

    L1CAM, a neural cell adhesion molecule, plays an important role in the development of the central nervous system. The human L1CAM gene is located in Xq28. Mutations in the gene are responsible for a wide spectrum of neurological abnormalities and mental retardation. Schizophrenia may result from early neurodevelopmental abnormalities. We screened 30 male and 30 female schizophrenic patients for their genomic sequence of the L1CAM gene in order to determine the DNA sequence variations. Three novel variations located in exon 18 (10564 G > A, GG/AA at codon 758), intron 11 (8575 A > C), and intron 25 (13504 C > T) were detected. An association study of the identified polymorphisms was then performed in a Japanese sample of 152 male and 115 female patients with schizophrenia and 121 male and 114 female control subjects. A statistically significant increase in the count of the 13504 T-allele was observed in the male patients, compared to the male controls, with no differences in the variations of exon 18 or intron 11. There was no statistically significant change in the distribution of allele or genotype of any variations in the female schizophrenics, in comparison with the female controls. These results suggest that the polymorphism in intron 25 plays a role in the genetic predisposition of male schizophrenia in the Japanese sample.

    American journal of medical genetics 2001;105;1;99-104

  • Spectrum and detection rate of L1CAM mutations in isolated and familial cases with clinically suspected L1-disease.

    Finckh U, Schröder J, Ressler B, Veske A and Gal A

    Department of Human Genetics, University Hospital Eppendorf, University of Hamburg, Hamburg, Germany.

    Mutations in L1CAM, the gene encoding the L1 neuronal cell adhesion molecule, lead to an X-linked trait characterized by one or more of the symptoms of hydrocephalus, adducted thumbs, agenesis or hypoplasia of corpus callosum, spastic paraplegia, and mental retardation (L1-disease). We screened 153 cases with prenatally or clinically suspected X-chromosomal hydrocephalus for L1CAM mutations by SSCP analysis of the 28 coding exons and regulatory elements in the 5'-untranslated region of the gene. Forty-six pathogenic mutations were found (30.1% detection rate), the majority consisting of nonsense, frameshift, and splice site mutations. In eight cases, segregation analysis disclosed recent de novo mutations. Statistical analysis of the data indicates a significant effect on mutation detection rate of (i) family history, (ii) number of L1-disease typical clinical findings, and (iii) presence or absence of signs not typically associated with L1CAM-disease. Whereas mutation detection rate was 74.2% for patients with at least two additional cases in the family, only 16 mutations were found in the 102 cases with negative family history (15.7% detection rate). Our data suggest a higher than previously assumed contribution of L1CAM mutations in the pathogenesis of the heterogeneous group of congenital hydrocephalus.

    American journal of medical genetics 2000;92;1;40-6

  • A silent mutation, C924T (G308G), in the L1CAM gene results in X linked hydrocephalus (HSAS).

    Du YZ, Dickerson C, Aylsworth AS and Schwartz CE

    J C Self Research Institute of Human Genetics, Greenwood Genetic Center, SC 29646, USA.

    The L1 cell adhesion molecule (L1CAM) is a neuronal gene involved in the development of the nervous system. Mutations in L1CAM are known to cause several clinically overlapping X linked mental retardation conditions: X linked hydrocephalus (HSAS), MASA syndrome (mental retardation, aphasia, shuffling gait, adducted thumbs), spastic paraplegia type I (SPG1), and X linked agenesis of the corpus callosum (ACC). In an analysis of a family with HSAS, we identified a C-->T transition (C924T) in exon 8 that was initially thought to have no effect on the protein sequence as the alteration affected the third base of a codon (G308G). Extensive analysis of the other 27 exons showed no other alteration. A review of the sequence surrounding position 924 indicated that the C-->T transition created a potential 5' splice site consensus sequence, which would result in an in frame deletion of 69 bp from exon 8 and 23 amino acids of the L1CAM protein. RT-PCR of the RNA from an affected male fetus and subsequent sequence analysis confirmed the use of the new splice site. This is the first report of a silent nucleotide substitution in L1CAM giving rise to an alteration at the protein level. Furthermore, it shows that as mutation analysis plays an ever more important role in human genetics, the identification of a synonymous base change should not be routinely discounted as a neutral polymorphism.

    Journal of medical genetics 1998;35;6;456-62

  • Genotype-phenotype correlation in L1 associated diseases.

    Fransen E, Van Camp G, D'Hooge R, Vits L and Willems PJ

    Department of Medical Genetics, University of Antwerp, Belgium.

    The neural cell adhesion molecule L1 (L1CAM) plays a key role during embryonic development of the nervous system and is involved in memory and learning. Mutations in the L1 gene are responsible for four X linked neurological conditions: X linked hydrocephalus (HSAS), MASA syndrome, complicated spastic paraplegia type 1 (SP-1), and X linked agenesis of the corpus callosum. As the clinical picture of these four L1 associated diseases shows considerable overlap and is characterised by Corpus callosum hypoplasia, mental Retardation, Adducted thumbs, Spastic paraplegia, and Hydrocephalus, these conditions have recently been lumped together into the CRASH syndrome. We investigate here whether a genotype-phenotype correlation exists in CRASH syndrome since its clinical spectrum is highly variable and numerous L1 mutations have been described. We found that (1) mutations in the extracellular part of L1 leading to truncation or absence of L1 cause a severe phenotype, (2) mutations in the cytoplasmic domain of L1 give rise to a milder phenotype than extracellular mutations, and (3) extracellular missense mutations affecting amino acids situated on the surface of a domain cause a milder phenotype than those affecting amino acids buried in the core of the domain.

    Journal of medical genetics 1998;35;5;399-404

  • Hydrocephalus and spastic paraplegia result from a donor splice site mutation (2872 + 1G to A) in the L1CAM gene in a Venezuelan pedigree.

    Claes S, Aguirre T, Simosa V, Bustos T, Lander R, Piras M, Legius E, Cassiman JJ and Raeymaekers P

    Center for Human Genetics, University of Leuven, Belgium.

    Human mutation 1998;Suppl 1;S240-1

  • Identification of novel L1CAM mutations using fluorescence-assisted mismatch analysis.

    Saugier-Veber P, Martin C, Le Meur N, Lyonnet S, Munnich A, David A, Hénocq A, Héron D, Jonveaux P, Odent S, Manouvrier S, Moncla A, Morichon N, Philip N, Satge D, Tosi M and Frébourg T

    Laboratoire de Génétique Moléculaire, CHU de Rouen, France.

    The L1CAM gene, which is located in Xq28 and codes for a neuronal cell adhesion molecule, is involved in three distinct conditions: HSAS (hydrocephalus-stenosis of the aqueduct of Sylvius), MASA (mental retardation, aphasia, shuffling gait, adductus thumbs), and SPG1 (spastic paraplegia). Molecular analysis of the L1CAM gene is labor-intensive because of the size of the coding region, which is fragmented in numerous exons, and because of the great allelic heterogeneity and distribution of the mutations. The FAMA (fluorescent assisted mismatch analysis) method combines the excellent sensitivity of the chemical cleavage method for scanning PCR fragments larger than 1 kb and the power of automated DNA sequencers. In order to optimize this method for L1CAM, we divided the gene into nine genomic fragments, each including three to four exons. These fragments were PCR-amplified using nine sets of primers containing additional rare universal sequences. A second-stage PCR, per formed with the two dye-labeled universal primers, allowed us to generate 1-kb-labeled fragments, which were then submitted to the chemical cleavage analysis. Among 12 French families with HSAS and/or MASA, we identified nine distinct L1CAM mutations, seven of which were novel, and an intronic variation. This study demonstrates that FAMA allows rapid and reliable detection of mutations in the L1CAM gene and thus represents one of the most appropriate methods to provide diagnosis for accurate genetic counseling in families with HSAS, MASA, or SPG1.

    Human mutation 1998;12;4;259-66

  • Multiple exon screening using restriction endonuclease fingerprinting (REF): detection of six novel mutations in the L1 cell adhesion molecule (L1CAM) gene.

    Du YZ, Srivastava AK and Schwartz CE

    J.C. Self Research Institute of Human Genetics, Greenwood Genetic Center, South Carolina 29646, USA.

    Restriction endonuclease fingerprinting (REF) has been utilized to screen 19 of the 28 exons in the L1CAM gene using only 5 PCR reactions. The clustered exons were amplified and the PCR products were subjected to endonuclease digestion and subsequent gel electrophoresis to produce a highly informative fingerprint for each PCR product. An alteration in the fingerprint, when compared to a control, determined the specific DNA fragment containing the mutation. Sequencing of the corresponding exon and flanking region was done to determine the precise location of the mutation. Using this method we have identified 6 novel mutations in the L1CAM gene in 5 patients with X-linked hydrocephalus and 2 patients with MASA. One of the mutations was common to both a patient with HSAS and a patient with MASA. The utilization of REF will allow for easier and quicker detection of mutations in the L1CAM gene. This method should be applicable for screening other genes with multiple, clustered exons.

    Human mutation 1998;11;3;222-30

  • L1CAM mutation in a Japanese family with X-linked hydrocephalus: a study for genetic counseling.

    Takahashi S, Makita Y, Okamoto N, Miyamoto A and Oki J

    Department of Pediatrics, Asahikawa Medical College, Nishikagura, Japan.

    Mutations in the gene encoding neural cell adhesion molecule L1 (L1CAM) are involved in X-linked hydrocephalus (HSAS, hydrocephalus due to stenosis of the aqueduct of Sylvius), MASA syndrome (mental retardation, aphasia, shuffling gait, and adducted thumbs), and spastic paraplegia type 1. We examined the L1CAM mutation in a Japanese family with HSAS for the purpose of DNA-based genetic counseling. The proband was a 9-year-old boy who had a 1-bp deletion in exon 22 of the L1CAM gene. This resulted in a shift of the reading frame, and introduction of a premature stop codon. Translation of this mRNA will create a truncated protein without the transmembrane domain, which cannot be expressed on the cell surface. Magnetic resonance images (MRI) revealed markedly enlarged lateral ventricles, hypoplastic white matter, thin cortical mantle, agenesis of the corpus callosum and septum pellucidum, and a fused thalamus. These findings represented impaired L1CAM function during development of the nervous system with resultant adhesion between neurons, neurites outgrowth and fasciculation, and neural cell migration. Screening by Apa I digestion of polymerase chain reaction (PCR) products identified the mother and the younger sister as heterozygous carriers. The carriers were asymptomatic. The father and the other sister did not have the mutation. The identification of L1CAM mutation in families with HSAS will give them the opportunity for DNA-based counseling and prenatal diagnosis.

    Brain & development 1997;19;8;559-62

  • Molecular analysis of the L1CAM gene in patients with X-linked hydrocephalus demonstrates eight novel mutations and suggests non-allelic heterogeneity of the trait.

    Gu SM, Orth U, Zankl M, Schröder J and Gal A

    Institut für Humangenetik, Universitäts-Krankenhaus Eppendorf, Hamburg, Germany.

    Eight novel mutations were identified in the gene encoding L1CAM, a neural cell adhesion protein, in patients/families with X-linked hydrocephalus (XHC) providing additional evidence for extreme allelic heterogeneity of the trait. The two nonsense mutations (Gln440Ter and Gln1042Ter) result most likely in functional null-alleles and complete absence of L1CAM at the cell surface. The four missense mutations (Leu482Pro, Ser542Pro, Met741Thr, and Val752Met) as well as delSer526 may considerably alter the structure of L1CAM. Interestingly, a missense mutation in an XHC family predicting the Val768Ile change in the second fibronectin type III domain of L1CAM was found not only in the two affected cousins and their obligate carrier mothers but also in two unaffected male relatives of the patients. Several possible explanations of this finding are discussed; the most likely being that Val768Ile is a rare non-pathogenic variant. If this were indeed the case, our data suggest that the XHC in this family is not due to a mutation of the L1CAM gene, i.e., that, in addition to the extreme allelic heterogeneity of XHC, a non-allelic form of genetic heterogeneity may also exist in this trait.

    American journal of medical genetics 1997;71;3;336-40

  • Hydrocephalus and Hirschsprung's disease in a patient with a mutation of L1CAM.

    Okamoto N, Wada Y and Goto M

    Department of Planning and Research, Osaka Medical Centre, Japan.

    Abnormalities of the L1CAM gene, a member of the immunoglobulin gene superfamily of neural cell adhesion molecules, are associated with X linked hydrocephalus and some allelic disorders. We describe a patient with X linked hydrocephalus and Hirschsprung's disease (HSCR) with a novel mutation in the L1CAM gene. This is the first report of HSCR with a mutant neural cell adhesion molecule. Although the disease phenotypes of this patient may well be independent, the alternative explanation that L1CAM mutations may contribute to both phenotypes cannot be excluded in view of an earlier report on another patient with both X linked hydrocephalus and HSCR.

    Journal of medical genetics 1997;34;8;670-1

  • Nine novel L1 CAM mutations in families with X-linked hydrocephalus.

    MacFarlane JR, Du JS, Pepys ME, Ramsden S, Donnai D, Charlton R, Garrett C, Tolmie J, Yates JR, Berry C, Goudie D, Moncla A, Lunt P, Hodgson S, Jouet M and Kenwrick S

    University of Cambridge Department of Medicine, Addenbrooke's Hospital, Cambridge, UK.

    Mutations in the gene for neural cell adhesion molecule L1 are responsible for the highly variable phenotype found in families with X-linked hydrocephalus, MASA syndrome, and spastic paraplegia type I. To date, 32 different mutations have been observed, the majority being unique to individual families. Here, we report nine novel mutations in L1 in 10 X-linked hydrocephalus families. Four mutations truncate the L1 protein and eliminate cell surface expression, and two would produce abnormal L1 through alteration of RNA processing. A further two of these mutations are small in-frame deletions that have occurred through a mechanism involving tandem repeated sequences. Together with a single missense mutation, these latter examples contribute to the growing number of existing mutations that affect short regions of the L1 protein that may have particular functional significance.

    Human mutation 1997;9;6;512-8

  • A novel mutation in L1CAM gene in a Japanese patient with X-linked hydrocephalus.

    Okamoto N, Wada Y, Kawabata H, Ishikiriyama S and Takahashi S

    Department of Planning and Research, Osaka Medical Center, Japan.

    L1CAM is a member of the immunoglobulin gene superfamily of neural adhesion molecule. Abnormality of the L1CAM gene is associated with X-linked recessive form of congenital hydrocephalus (HSAS; hydrocephalus due to congenital stenosis of aqueduct of Sylvius) and some allelic disorders. Four new patients with congenital hydrocephalus consistent with the X-linked type were described. One of them had a novel mutation in the L1CAM gene.

    The Japanese journal of human genetics 1996;41;4;431-7

  • A deletion of five nucleotides in the L1CAM gene in a Japanese family with X-linked hydrocephalus.

    Takechi T, Tohyama J, Kurashige T, Maruta K, Uyemura K, Ohi T, Matsukura S and Sakuragawa N

    Department of Inherited Metabolic Disease, National Institute of Neuroscience, Tokyo, Japan.

    X-linked hydrocephalus (HSAS) is the most common form of inherited hydrocephalus characterized by hydrocephalus due to stenosis of the aqueduct of Sylvius, mental retardation, clasped thumbs, and spastic paraparesis. MASA syndrome (mental retardation, aphasia, shuffling gait and adducted thumbs) and SPG1 (X-linked complicated spastic paraplegia) are also X-linked disorders with overlapping clinical signs. Linkage analysis studies implicated the neural cell adhesion molecule L1 (L1CAM) gene as a candidate gene for these X-linked disorders. This genetic study analyzes the L1CAM gene in a Japanese family with members suffering from HSAS, and describes a deletion of five nucleotides in exon 8. Screening by Bg1I digestion of polymerase chain reaction (PCR) products revealed that two siblings have the same mutation and a sister was identified as a heterozygous carrier. The 5 nucleotide deletion causes a shift of the reading frame and introduces a premature stop codon 72 nucleotides downstream, which might result in a truncated protein. The mutation identified herein is a novel L1CAM mutation, which triggers hydrocephalus. We report a unique L1CAM mutation that causes HSAS: the first report of such a mutation in a Japanese family.

    Human genetics 1996;97;3;353-6

  • Discordant segregation of Xq28 markers and a mutation in the L1 gene in a family with X linked hydrocephalus.

    Jouet M, Strain L, Bonthron D and Kenwrick S

    Department of Medicine, University of Cambridge, UK.

    X linked recessive hydrocephalus is the most common hereditary form of hydrocephalus. Genetic analysis indicates that the majority of cases are caused by mutations in a single gene in Xq28, recently identified as the gene for neural cell adhesion molecule L1. Genetic heterogeneity for this disorder was suggested following the description of a single large pedigree where X linked hydrocephalus showed lack of linkage to Xq28 markers flanking the L1 gene. Mutation analysis in this family shows a single base pair deletion within the coding sequence of the L1 gene that would result in truncation of the mature protein. The nature of the mutation and its segregation with the disease through the pedigree indicate that it is the cause of X linked hydrocephalus in this family. These results are at odds with data obtained through segregation of alleles for markers flanking the L1 gene. Somatic and germline mosaicism is the most plausible explanation for these data, which also provide further evidence for genetic homogeneity of X linked hydrocephalus.

    Journal of medical genetics 1996;33;3;248-50

  • [A family with X-linked hydrocephalus resulting from mutations in the neural cell adhesion molecule L1].

    Maruta K, Ohi T, Ohdo S, Takechi T, Sakuragawa N and Matsukura S

    Division of Neurology, National Nichinan Hospital, Miyazaki, Japan.

    We present the two siblings with X-linked hydrocephalus (XLH) and discuss the clinical features and genetical analysis of them. Case 1. The proband, a male, was delivered by the emergency cesarean section because of enlarged head circumference (44cm). His head circumference at 24 years old was 92cm. Neurological examination revealed adducted thumbs, horizontal nystagmus, hyperreflexia and spasticity of legs. He had tonic convulsions. MRI revealed a very thin layer of cerebral cortex. Molecular analysis revealed a deletion of 5 bases in exon 8 of the cell adhesion molecule L1 (L1CAM) gene located at chromosome Xq28. Case 2. The younger maternal half brother of case 1 was also born by the cesarean section, with 48cm in head circumference. A ventriculoatrial shunt was placed at the first month old. Epileptic seizures were seen. At the age of 21 years he had a head circumference of 59cm. A physical examination showed bilateral adducted thumbs, upward deviation of eyes, hyperreflexia and spasticity of legs. CT showed marked generalized ventricular enlargement including the fourth ventricle. Molecular analysis confirmed the same mutations as that of case 1. A maternal uncle had a previous diagnosis of hydrocephalus, and a sister is identified as a heterozygous carrier from molecular genetical analysis. Our results indicate that HLX is caused by the mutations in the gene for neural L1CAM in our family.

    Rinsho shinkeigaku = Clinical neurology 1996;36;3;462-6

  • Five novel mutations in the L1CAM gene in families with X linked hydrocephalus.

    Gu SM, Orth U, Veske A, Enders H, Klunder K, Schlosser M, Engel W, Schwinger E and Gal A

    Institut fur Humangenetik, Medizinische Universitat zu Lubeck, Germany.

    Five novel mutations have been identified in the gene encoding L1CAM, a neural cell adhesion protein, in families with X linked hydrocephalus (XHC). Interestingly, all five mutations are in the evolutionarily highly conserved Ig-like domains of the protein. The two frameshift mutations (52insC and 955delG) and the nonsense mutation (Trp276Ter) most probably result in functional null alleles and complete absence of L1CAM at the cell surface. The two missense mutations (Tyr194Cys and Pro240Leu) may considerably alter the structure of the L1CAM protein. These data provide convincing evidence that XHC is genetically extremely heterogeneous.

    Journal of medical genetics 1996;33;2;103-6

  • Mutations in L1-CAM in two families with X linked complicated spastic paraplegia, MASA syndrome, and HSAS.

    Ruiz JC, Cuppens H, Legius E, Fryns JP, Glover T, Marynen P and Cassiman JJ

    Centre for Human Genetics, University of Leuven, Belgium.

    The suggestion that the three X linked syndromes X linked spastic paraplegia (MIM 312900), MASA syndrome (MIM 303350), and X linked hydrocephalus owing to stenosis of the aqueduct of Sylvius (MIM 307000) are variable clinical manifestations of mutations at the same locus at Xq28 was confirmed by the finding of mutations in the L1-CAM gene in the three syndromes. Recently, two families in which different subjects showed a clearly different phenotype within the same family of the three X linked syndromes were described. A reverse transcription PCR assay was developed for the analysis of the L1-CAM cDNA in two of the members of these families. RNA isolated from EBV transformed cell lines and a colon carcinoma derived cell line was used as a starting material. The L1-CAM cDNA of two male patients from each family was sequenced. We report two new mutations in the L1-CAM gene in these two families showing that the three different phenotypes observed in different generations within the same family are variable phenotypic expressions of the same mutation.

    Journal of medical genetics 1995;32;7;549-52

  • New domains of neural cell-adhesion molecule L1 implicated in X-linked hydrocephalus and MASA syndrome.

    Jouet M, Moncla A, Paterson J, McKeown C, Fryer A, Carpenter N, Holmberg E, Wadelius C and Kenwrick S

    University of Cambridge Department of Medicine, Addenbrooke's Hospital, United Kingdom.

    The neural cell-adhesion molecule L1 is involved in intercellular recognition and neuronal migration in the CNS. Recently, we have shown that mutations in the gene encoding L1 are responsible for three related disorders; X-linked hydrocephalus, MASA (mental retardation, aphasia, shuffling gait, and adducted thumbs) syndrome, and spastic paraplegia type I (SPG1). These three disorders represent a clinical spectrum that varies not only between families but sometimes also within families. To date, 14 independent L1 mutations have been reported and shown to be disease causing. Here we report nine novel L1 mutations in X-linked hydrocephalus and MASA-syndrome families, including the first examples of mutations affecting the fibronectin type III domains of the molecule. They are discussed in relation both to phenotypes and to the insights that they provide into L1 function.

    American journal of human genetics 1995;56;6;1304-14

  • X-linked hydrocephalus and MASA syndrome present in one family are due to a single missense mutation in exon 28 of the L1CAM gene.

    Fransen E, Schrander-Stumpel C, Vits L, Coucke P, Van Camp G and Willems PJ

    Department of Medical Genetics, University of Antwerp-UIA, Belgium.

    Human molecular genetics 1994;3;12;2255-6

  • MASA syndrome is due to mutations in the neural cell adhesion gene L1CAM.

    Vits L, Van Camp G, Coucke P, Fransen E, De Boulle K, Reyniers E, Korn B, Poustka A, Wilson G, Schrander-Stumpel C et al.

    Department of Medical Genetics, University of Antwerp, Belgium.

    MASA syndrome is a recessive X-linked disorder characterized by mental retardation, adducted thumbs, shuffling gait, aphasia and, in some cases, hydrocephalus. Since it has been shown that X-linked hydrocephalus can be caused by mutations in L1CAM, a neuronal cell adhesion molecule, we performed an L1CAM mutation analysis in eight unrelated patients with MASA syndrome. Three different L1CAM mutations were identified: a deletion removing part of the open reading frame and two point mutations resulting in amino acid substitutions. L1CAM, therefore, harbours mutations leading to either MASA syndrome or HSAS, and might be frequently implicated in X-linked mental retardation with or without hydrocephalus.

    Nature genetics 1994;7;3;408-13

  • X-linked spastic paraplegia (SPG1), MASA syndrome and X-linked hydrocephalus result from mutations in the L1 gene.

    Jouet M, Rosenthal A, Armstrong G, MacFarlane J, Stevenson R, Paterson J, Metzenberg A, Ionasescu V, Temple K and Kenwrick S

    Department of Medicine, University of Cambridge, Addenbrooke's Hospital, UK.

    X-linked hydrocephalus, spastic paraplegia type I and MASA syndrome are related disorders with loci in subchromosomal region Xq28. We have previously shown that X-linked hydrocephalus is caused by mutations in the gene for neural cell adhesion molecule L1 (L1CAM), an axonal glycoprotein involved in neuronal migration and differentiation. Here we report mutations of the L1 gene in MASA syndrome and SPG1, in addition to HSAS families. Two of the HSAS mutations would abolish cell surface expression of L1 and represent the first functional null mutations in this disorder. Our results indicate that these three syndromes from part of a clinical spectrum resulting from a heterogeneous group of mutations in the L1 gene.

    Nature genetics 1994;7;3;402-7

  • Identification of a 5' splice site mutation in intron 4 of the L1CAM gene in an X-linked hydrocephalus family.

    Coucke P, Vits L, Van Camp G, Serville F, Lyonnet S, Kenwrick S, Rosenthal A, Wehnert M, Munnich A and Willems PJ

    Department of Medical Genetics, University of Antwerp-UIA, Belgium.

    Human molecular genetics 1994;3;4;671-3

  • A duplication in the L1CAM gene associated with X-linked hydrocephalus.

    Van Camp G, Vits L, Coucke P, Lyonnet S, Schrander-Stumpel C, Darby J, Holden J, Munnich A and Willems PJ

    Department of Medical Genetics, University of Antwerp-UIA, Belgium.

    Recently, a mutation in the gene for the neural cell adhesion molecule L1CAM, located at chromosome Xq28, was found in a family with X-linked hydrocephalus (HSAS). However, as the L1CAM mutation could only be identified in one HSAS family, it remained unclear whether or not L1CAM was the gene responsible for HSAS. We have conducted a mutation analysis of L1CAM in 25 HSAS families. The mutation reported previously was not found in any of these families. In one family, however, a 1.3 kilobases (kb) genomic duplication was identified, cosegregating with HSAS and significantly changing the intracellular domain of the L1CAM protein. These results confirm that L1CAM is the HSAS gene.

    Nature genetics 1993;4;4;421-5

  • Aberrant splicing of neural cell adhesion molecule L1 mRNA in a family with X-linked hydrocephalus.

    Rosenthal A, Jouet M and Kenwrick S

    Department of Medicine, University of Cambridge, Addenbrooke's Hospital, UK.

    A locus for X-linked hydrocephalus (HSAS), which is characterized by mental retardation and enlarged brain ventricles, maps to the same subchromosomal region (Xq28) as the gene for neural cell adhesion molecule L1. We have found novel L1 mRNA species in cells from affected members of a HSAS family containing deletions and insertions produced by the utilization of alternative 3' splice sites. A point mutation at a potential branch point signal in an intron segregates with the disease and is likely to be responsible for the abnormal RNA processing. These results suggest that HSAS is a disorder of neuronal cell migration due to disruption of L1 protein function.

    Nature genetics 1992;2;2;107-12

Literature (141)

Pubmed - human_disease

  • L1CAM mutation in a boy with hydrocephalus and duplex kidneys.

    Liebau MC, Gal A, Superti-Furga A, Omran H and Pohl M

    Department of Pediatrics and Adolescent Medicine, University Hospital of Freiburg, Mathildenstrasse 1, 79106, Freiburg, Germany.

    Mutations in the X-chromosomal gene (L1CAM) for cell adhesion molecule L1 are associated with a heterogeneous group of conditions that include agenesis of the corpus callosum, hydrocephalus, spastic paraplegia, adducted thumbs and mental retardation (L1-spectrum disease, CRASH or MASA syndrome). Although L1CAM is expressed during renal development and L1cam-deficient mice have congenital malformations of the kidney and the urinary tract, L1CAM mutations have not been associated with renal anomalies in men. We report on a boy with prenatally detected hydrocephalus. After his birth, bilateral duplex kidneys and ureters, with a unilateral mega-ureter serving a hydronephrotic upper pole, as well as agenesis of the corpus callosum, adducted thumbs, spasticity, and mental retardation were recognized, fulfilling the criteria of an L1-spectrum disease. Genetic testing of the patient and his mother identified a 2 bp deletion in the invariant splice consensus sequence of intron 18 of L1CAM, predicting a largely truncated or absent protein. At the age of 9 years, 7 years after heminephrectomy, the boy has normal renal function. This observation suggests that patients with L1CAM mutations may have renal abnormalities as seen in the L1cam-deficient mouse model. L1CAM might, therefore, also be considered a possible candidate gene for renal malformations.

    Pediatric nephrology (Berlin, Germany) 2007;22;7;1058-61

  • Contiguous gene deletion involving L1CAM and AVPR2 causes X-linked hydrocephalus with nephrogenic diabetes insipidus.

    Tegay DH, Lane AH, Roohi J and Hatchwell E

    Stony Brook University Hospital, Stony Brook, New York, USA. david.tegay@stonybrook.edu

    X-linked hydrocephalus with aqueductal stenosis (HSAS) is caused by mutation or deletion of the L1 cell adhesion molecule gene (L1CAM) at Xq28. Central diabetes insipidus (CDI) can arise as a consequence of resultant hypothalamic dysfunction from hydrocephalus and must be distinguished from nephrogenic diabetes insipidus (NDI) by exogenous vasopressin response. Causes of NDI are heterogeneous and include mutation or deletion of the arginine vasopressin receptor 2 gene (AVPR2), which is located approximately 29 kb telomeric to L1CAM. We identified a patient with both HSAS and NDI where DNA sequencing failure suggested the possibility of a contiguous gene deletion. A 32.7 kb deletion mapping from L1CAM intron1 to AVPR2 exon2 was confirmed. A 90 bp junctional insertion fragment sharing short direct repeat homology with flanking sequences was identified. To our knowledge this is the first reported case of an Xq28 microdeletion involving both L1CAM and AVPR2, defining a new contiguous gene syndrome comprised of HSAS and NDI. Contiguous gene deletion should be considered as a mechanism for all patients presenting with hydrocephalus and NDI.

    Funded by: NIGMS NIH HHS: T32 GM008444

    American journal of medical genetics. Part A 2007;143A;6;594-8

  • Prenatal diagnosis in a family with X-linked hydrocephalus.

    Panayi M, Gokhale D, Mansour S and Elles R

    National Genetics Reference Laboratory, Regional Genetics Service, St Mary's Hospital, Manchester, UK. maria.panayi@cmmc.nhs.uk

    The neural cell adhesion molecule L1 is a transmembrane glycoprotein belonging to the immunoglobulin superfamily of cell adhesion molecules (CAMs). Its expression is essential during embryonic development of the nervous system and it is involved in cognitive function and memory. Mutations in the L1CAM gene are responsible for four related L1 disorders; X-linked hydrocephalus/HSAS (Hydrocephalus as a result of Stenosis of the Aqueduct of Sylvius), MASA (Mental retardation, Aphasia, Shuffling gait, and Adducted thumbs) syndrome, X-linked complicated spastic paraplegia type I (SPG1) and X-linked Agenesis of the Corpus Callosum (ACC). These four disorders represent a clinical spectrum that varies both between and within families. The main clinical features of this spectrum are Corpus callosum hypoplasia, mental Retardation, Adducted thumbs, Spastic paraplegia and Hydrocephalus (CRASH syndrome). Since there is no biochemically assayed disease marker, molecular analysis of the L1CAM gene is the only means of confirming a clinical diagnosis. Most L1CAM mutations reported to date are point mutations (missense, nonsense, splice site) and only a few patients with larger rearrangements have been documented. We have characterised a rare intragenic deletion of the L1CAM gene in a sample of DNA extracted from a chorionic villus biopsy (CVB) performed at 12 weeks' gestation. =

    Prenatal diagnosis 2005;25;10;930-3

  • First case of L1CAM gene mutation identified in MASA syndrome in Asia.

    Kanemura Y, Takuma Y, Kamiguchi H and Yamasaki M

    Institute for Clinical Research, Osaka National Hospital, National Hospital Organization, Osaka 540-0006, Japan.

    We report here the first case of an L1CAM gene mutation identified in mental retardation, adducted thumbs, shuffling gait, and aphasia (MASA) syndrome in Japan. The patient was a 10-year-old boy with mild mental retardation, bilateral adducted thumbs and corpus callosum hypoplasia. His family had no history of MASA syndrome. The L1CAM gene contained a nonsense mutation (R1166X) in exon 26 in the cytoplasmic domain. No mutation was found in the extracellular and transmembrane domains of L1CAM. The abnormal development of axon tracts resulting in the corpus callosum hypoplasia and adducted thumbs appears to be caused by malfunction of the cytoplasmic domain of L1CAM.

    Congenital anomalies 2005;45;2;67-9

  • A novel L1CAM mutation with L1 spectrum disorders.

    Silan F, Ozdemir I and Lissens W

    Medical Biology and Genetic Department, Abant Izzet Baysal University, Duzce School of Medicine, Duzce, Turkey. fsilan@yahoo.com

    X-linked hydrocephalus, HSAS (hydrocephalus due to stenosis of aqueduct of Sylvius), MASA (mental retardation, aphasia, shuffling gait, and adducted thumbs), and CRASH (corpus callosum hypoplasia, retardation, adducted thumbs, spastic paraplegia, and hydrocephalus) syndromes are allelic disorders. X-linked hydrocephalus and associated phenotypes are due to mutations in the L1CAM gene, which has been identified as a coding neural cell adhesion molecule. We report two cases of L1 spectrum disorders within the same family. The first case was diagnosed by ultrasonographic examination prenatally and the second case was diagnosed postnatally. Both patients and their mothers carry a novel mutation of the L1CAM gene. In this family, nine X-linked hydrocephalus and five female carriers were found in three generations, and molecular genetic analysis was performed to detect the asymptomatic carriers.

    Prenatal diagnosis 2005;25;1;57-9

  • LGI1 gene mutation screening in sporadic partial epilepsy with auditory features.

    Flex E, Pizzuti A, Di Bonaventura C, Douzgou S, Egeo G, Fattouch J, Manfredi M, Dallapiccola B and Giallonardo AT

    Dipartimento di Medicina Sperimentale e Patologia, Universita' di Roma La Sapienza, Rome, Italy.

    Partial epilepsy with auditory features occasionally segregates in families as an autosomal dominant trait. In some families mutations in the leucine-rich glioma inactivated (LGI1) gene have been identified. Sporadic cases might harbour either denovo or low-penetrant LGI1 mutations, which will substantially alter the family risk for epilepsy. We selected sixteen sporadic patients with cryptogenic temporal lobe epilepsy and partial seizures with auditory features. We compared clinical features of these patients with those of published autosomal dominant family cases. We screened these patients for LGI1 mutations. Comparing the sporadic patients with the published familial cases no difference in either the primary auditory features or in the other associated epileptic manifestations was identified. Sequence analysis of the whole LGI1 gene coding regions in sporadic patients did not reveal changes in the LGI1 gene. The genetic analysis demonstrates that LGI1 is not a major gene for sporadic cases of partial epilepsy with auditory features at least in the Italian population. Screening of sporadic patients for LGI1 mutations appears not useful in genetic counselling of these patients.

    Journal of neurology 2005;252;1;62-6

  • Intronic mutations in the L1CAM gene may cause X-linked hydrocephalus by aberrant splicing.

    Hübner CA, Utermann B, Tinschert S, Krüger G, Ressler B, Steglich C, Schinzel A and Gal A

    Institute of Human Genetics, University Hospital Eppendorf, Hamburg, Germany. c.huebner@uke.uni-hamburg.de

    L1 disease is a clinically heterogeneous X-chromosomal neurodevelopmental disorder that is frequently associated with mental retardation and congenital hydrocephalus in males. It is caused by mutations in L1CAM that encodes a multifunctional transmembrane neuronal cell adhesion molecule. We report our findings on 6 novel intronic L1CAM sequence variants (c.523+5G>A, c.1123+1G>A, c.1547-13delC, c.3323-17dupG, c.3457+3A>T, and c.3457+18C>T), and a recurrent one (c.523+12C>T). While the pathogenic potential of nucleotide changes within the evolutionarily well-conserved splice consensus sequence (c.523+5G>A, c.1123+1G>A, and c.3457+3A>T) is widely accepted, it is not always straight forward to assess the disease relevance of intronic mutations, if they lie outside the consensus. The c.523+12C>T variant co-segregated with X-linked hydrocephalus in two unrelated families. In the mutated allele, a preferentially used novel splice donor site is generated that results in a frame shift due to insertion of the first 10 bp of intron 5 in the mature mRNA, a largely truncated protein, and most likely a functional null allele. The c.1547-13delC mutation creates a new acceptor site resulting in the insertion of 4 additional amino acids at the end of the immunoglobulin like domain 5. In contrast, c.3323-17dupG and c.3457+18C>T seem to be non-pathogenic L1CAM variants.

    Human mutation 2004;23;5;526

  • [A family with autosomal dominant temporal lobe epilepsy accompanied by motor and sensory neuropathy].

    Matsuoka T, Furuya H, Ikezoe K, Murai H, Ohyagi Y, Yoshiura T, Sasaki M, Tobimatsu S and Kira J

    Department of Neurology, Graduate School of Medical Sciences, Kyushu University.

    We report a 20-year-old man with temporal lobe epilepsy (TLE) accompanied by hereditary motor and sensory neuropathy (HMSN). He had experienced complex partial seizures (CPS), which started with a nausea-like feeling, followed by loss of consciousness and automatism, since he was 6 years old. The frequency of attacks was at first decreased by phenytoin. However, attacks increased again when he was 18 years old. On admission, neurological examination showed mild weakness of the toes, pes cavus, hammer toe and mildly impaired vibratory sensation in his legs. Ten people in four generations of his family showed a history of epilepsy in the autosomal dominant inheritance form. His younger sister and mother had a history of epilepsy accompanied with pes cavus, hammer toe, weakness of toe and finger extension and mildly impaired vibratory sensation as well. Direct sequencing of the glioma-inactivated leucine-rich gene (LGI1), in which several mutations were reported in patients with familial lateral temporal lobe epilepsy, showed no specific mutation in this family. On consecutive video-EEG monitoring, paroxysmal rhythmic activity was confirmed in his left fronto-temporal region when he showed automatism, and then a generalized slow burst activity was detected when he lost consciousness. For his seizures, TLE with secondary generalization was diagnosed. In the nerve conduction study, delayed nerve conduction, distal motor latency and decreased amplitudes of the compound muscle action potentials (CMAP) of bilateral peroneal nerves were observed, indicating the existence of mild axonal degeneration. Based on these data, we consider that this family to be a new phenotype of autosomal dominant TLE accompanied by motor and sensory neuropathy.

    Rinsho shinkeigaku = Clinical neurology 2004;44;1;43-9

  • An association study between polymorphism of L1CAM gene and schizophrenia in a Japanese sample.

    Kurumaji A, Nomoto H, Okano T and Toru M

    Department of Neuropsychiatry, Tokyo Medical and Dental University School of Medicine, Japan. 0724.psyc@med.tmd.ac.jp

    L1CAM, a neural cell adhesion molecule, plays an important role in the development of the central nervous system. The human L1CAM gene is located in Xq28. Mutations in the gene are responsible for a wide spectrum of neurological abnormalities and mental retardation. Schizophrenia may result from early neurodevelopmental abnormalities. We screened 30 male and 30 female schizophrenic patients for their genomic sequence of the L1CAM gene in order to determine the DNA sequence variations. Three novel variations located in exon 18 (10564 G > A, GG/AA at codon 758), intron 11 (8575 A > C), and intron 25 (13504 C > T) were detected. An association study of the identified polymorphisms was then performed in a Japanese sample of 152 male and 115 female patients with schizophrenia and 121 male and 114 female control subjects. A statistically significant increase in the count of the 13504 T-allele was observed in the male patients, compared to the male controls, with no differences in the variations of exon 18 or intron 11. There was no statistically significant change in the distribution of allele or genotype of any variations in the female schizophrenics, in comparison with the female controls. These results suggest that the polymorphism in intron 25 plays a role in the genetic predisposition of male schizophrenia in the Japanese sample.

    American journal of medical genetics 2001;105;1;99-104

  • A silent mutation, C924T (G308G), in the L1CAM gene results in X linked hydrocephalus (HSAS).

    Du YZ, Dickerson C, Aylsworth AS and Schwartz CE

    J C Self Research Institute of Human Genetics, Greenwood Genetic Center, SC 29646, USA.

    The L1 cell adhesion molecule (L1CAM) is a neuronal gene involved in the development of the nervous system. Mutations in L1CAM are known to cause several clinically overlapping X linked mental retardation conditions: X linked hydrocephalus (HSAS), MASA syndrome (mental retardation, aphasia, shuffling gait, adducted thumbs), spastic paraplegia type I (SPG1), and X linked agenesis of the corpus callosum (ACC). In an analysis of a family with HSAS, we identified a C-->T transition (C924T) in exon 8 that was initially thought to have no effect on the protein sequence as the alteration affected the third base of a codon (G308G). Extensive analysis of the other 27 exons showed no other alteration. A review of the sequence surrounding position 924 indicated that the C-->T transition created a potential 5' splice site consensus sequence, which would result in an in frame deletion of 69 bp from exon 8 and 23 amino acids of the L1CAM protein. RT-PCR of the RNA from an affected male fetus and subsequent sequence analysis confirmed the use of the new splice site. This is the first report of a silent nucleotide substitution in L1CAM giving rise to an alteration at the protein level. Furthermore, it shows that as mutation analysis plays an ever more important role in human genetics, the identification of a synonymous base change should not be routinely discounted as a neutral polymorphism.

    Journal of medical genetics 1998;35;6;456-62

  • Genotype-phenotype correlation in L1 associated diseases.

    Fransen E, Van Camp G, D'Hooge R, Vits L and Willems PJ

    Department of Medical Genetics, University of Antwerp, Belgium.

    The neural cell adhesion molecule L1 (L1CAM) plays a key role during embryonic development of the nervous system and is involved in memory and learning. Mutations in the L1 gene are responsible for four X linked neurological conditions: X linked hydrocephalus (HSAS), MASA syndrome, complicated spastic paraplegia type 1 (SP-1), and X linked agenesis of the corpus callosum. As the clinical picture of these four L1 associated diseases shows considerable overlap and is characterised by Corpus callosum hypoplasia, mental Retardation, Adducted thumbs, Spastic paraplegia, and Hydrocephalus, these conditions have recently been lumped together into the CRASH syndrome. We investigate here whether a genotype-phenotype correlation exists in CRASH syndrome since its clinical spectrum is highly variable and numerous L1 mutations have been described. We found that (1) mutations in the extracellular part of L1 leading to truncation or absence of L1 cause a severe phenotype, (2) mutations in the cytoplasmic domain of L1 give rise to a milder phenotype than extracellular mutations, and (3) extracellular missense mutations affecting amino acids situated on the surface of a domain cause a milder phenotype than those affecting amino acids buried in the core of the domain.

    Journal of medical genetics 1998;35;5;399-404

  • Hydrocephalus and spastic paraplegia result from a donor splice site mutation (2872 + 1G to A) in the L1CAM gene in a Venezuelan pedigree.

    Claes S, Aguirre T, Simosa V, Bustos T, Lander R, Piras M, Legius E, Cassiman JJ and Raeymaekers P

    Center for Human Genetics, University of Leuven, Belgium.

    Human mutation 1998;Suppl 1;S240-1

  • L1CAM mutation in a Japanese family with X-linked hydrocephalus: a study for genetic counseling.

    Takahashi S, Makita Y, Okamoto N, Miyamoto A and Oki J

    Department of Pediatrics, Asahikawa Medical College, Nishikagura, Japan.

    Mutations in the gene encoding neural cell adhesion molecule L1 (L1CAM) are involved in X-linked hydrocephalus (HSAS, hydrocephalus due to stenosis of the aqueduct of Sylvius), MASA syndrome (mental retardation, aphasia, shuffling gait, and adducted thumbs), and spastic paraplegia type 1. We examined the L1CAM mutation in a Japanese family with HSAS for the purpose of DNA-based genetic counseling. The proband was a 9-year-old boy who had a 1-bp deletion in exon 22 of the L1CAM gene. This resulted in a shift of the reading frame, and introduction of a premature stop codon. Translation of this mRNA will create a truncated protein without the transmembrane domain, which cannot be expressed on the cell surface. Magnetic resonance images (MRI) revealed markedly enlarged lateral ventricles, hypoplastic white matter, thin cortical mantle, agenesis of the corpus callosum and septum pellucidum, and a fused thalamus. These findings represented impaired L1CAM function during development of the nervous system with resultant adhesion between neurons, neurites outgrowth and fasciculation, and neural cell migration. Screening by Apa I digestion of polymerase chain reaction (PCR) products identified the mother and the younger sister as heterozygous carriers. The carriers were asymptomatic. The father and the other sister did not have the mutation. The identification of L1CAM mutation in families with HSAS will give them the opportunity for DNA-based counseling and prenatal diagnosis.

    Brain & development 1997;19;8;559-62

  • Hydrocephalus and Hirschsprung's disease in a patient with a mutation of L1CAM.

    Okamoto N, Wada Y and Goto M

    Department of Planning and Research, Osaka Medical Centre, Japan.

    Abnormalities of the L1CAM gene, a member of the immunoglobulin gene superfamily of neural cell adhesion molecules, are associated with X linked hydrocephalus and some allelic disorders. We describe a patient with X linked hydrocephalus and Hirschsprung's disease (HSCR) with a novel mutation in the L1CAM gene. This is the first report of HSCR with a mutant neural cell adhesion molecule. Although the disease phenotypes of this patient may well be independent, the alternative explanation that L1CAM mutations may contribute to both phenotypes cannot be excluded in view of an earlier report on another patient with both X linked hydrocephalus and HSCR.

    Journal of medical genetics 1997;34;8;670-1

  • A novel mutation in L1CAM gene in a Japanese patient with X-linked hydrocephalus.

    Okamoto N, Wada Y, Kawabata H, Ishikiriyama S and Takahashi S

    Department of Planning and Research, Osaka Medical Center, Japan.

    L1CAM is a member of the immunoglobulin gene superfamily of neural adhesion molecule. Abnormality of the L1CAM gene is associated with X-linked recessive form of congenital hydrocephalus (HSAS; hydrocephalus due to congenital stenosis of aqueduct of Sylvius) and some allelic disorders. Four new patients with congenital hydrocephalus consistent with the X-linked type were described. One of them had a novel mutation in the L1CAM gene.

    The Japanese journal of human genetics 1996;41;4;431-7

  • A deletion of five nucleotides in the L1CAM gene in a Japanese family with X-linked hydrocephalus.

    Takechi T, Tohyama J, Kurashige T, Maruta K, Uyemura K, Ohi T, Matsukura S and Sakuragawa N

    Department of Inherited Metabolic Disease, National Institute of Neuroscience, Tokyo, Japan.

    X-linked hydrocephalus (HSAS) is the most common form of inherited hydrocephalus characterized by hydrocephalus due to stenosis of the aqueduct of Sylvius, mental retardation, clasped thumbs, and spastic paraparesis. MASA syndrome (mental retardation, aphasia, shuffling gait and adducted thumbs) and SPG1 (X-linked complicated spastic paraplegia) are also X-linked disorders with overlapping clinical signs. Linkage analysis studies implicated the neural cell adhesion molecule L1 (L1CAM) gene as a candidate gene for these X-linked disorders. This genetic study analyzes the L1CAM gene in a Japanese family with members suffering from HSAS, and describes a deletion of five nucleotides in exon 8. Screening by Bg1I digestion of polymerase chain reaction (PCR) products revealed that two siblings have the same mutation and a sister was identified as a heterozygous carrier. The 5 nucleotide deletion causes a shift of the reading frame and introduces a premature stop codon 72 nucleotides downstream, which might result in a truncated protein. The mutation identified herein is a novel L1CAM mutation, which triggers hydrocephalus. We report a unique L1CAM mutation that causes HSAS: the first report of such a mutation in a Japanese family.

    Human genetics 1996;97;3;353-6

  • [A family with X-linked hydrocephalus resulting from mutations in the neural cell adhesion molecule L1].

    Maruta K, Ohi T, Ohdo S, Takechi T, Sakuragawa N and Matsukura S

    Division of Neurology, National Nichinan Hospital, Miyazaki, Japan.

    We present the two siblings with X-linked hydrocephalus (XLH) and discuss the clinical features and genetical analysis of them. Case 1. The proband, a male, was delivered by the emergency cesarean section because of enlarged head circumference (44cm). His head circumference at 24 years old was 92cm. Neurological examination revealed adducted thumbs, horizontal nystagmus, hyperreflexia and spasticity of legs. He had tonic convulsions. MRI revealed a very thin layer of cerebral cortex. Molecular analysis revealed a deletion of 5 bases in exon 8 of the cell adhesion molecule L1 (L1CAM) gene located at chromosome Xq28. Case 2. The younger maternal half brother of case 1 was also born by the cesarean section, with 48cm in head circumference. A ventriculoatrial shunt was placed at the first month old. Epileptic seizures were seen. At the age of 21 years he had a head circumference of 59cm. A physical examination showed bilateral adducted thumbs, upward deviation of eyes, hyperreflexia and spasticity of legs. CT showed marked generalized ventricular enlargement including the fourth ventricle. Molecular analysis confirmed the same mutations as that of case 1. A maternal uncle had a previous diagnosis of hydrocephalus, and a sister is identified as a heterozygous carrier from molecular genetical analysis. Our results indicate that HLX is caused by the mutations in the gene for neural L1CAM in our family.

    Rinsho shinkeigaku = Clinical neurology 1996;36;3;462-6

  • Discordant segregation of Xq28 markers and a mutation in the L1 gene in a family with X linked hydrocephalus.

    Jouet M, Strain L, Bonthron D and Kenwrick S

    Department of Medicine, University of Cambridge, UK.

    X linked recessive hydrocephalus is the most common hereditary form of hydrocephalus. Genetic analysis indicates that the majority of cases are caused by mutations in a single gene in Xq28, recently identified as the gene for neural cell adhesion molecule L1. Genetic heterogeneity for this disorder was suggested following the description of a single large pedigree where X linked hydrocephalus showed lack of linkage to Xq28 markers flanking the L1 gene. Mutation analysis in this family shows a single base pair deletion within the coding sequence of the L1 gene that would result in truncation of the mature protein. The nature of the mutation and its segregation with the disease through the pedigree indicate that it is the cause of X linked hydrocephalus in this family. These results are at odds with data obtained through segregation of alleles for markers flanking the L1 gene. Somatic and germline mosaicism is the most plausible explanation for these data, which also provide further evidence for genetic homogeneity of X linked hydrocephalus.

    Journal of medical genetics 1996;33;3;248-50

  • Identification of a 5' splice site mutation in intron 4 of the L1CAM gene in an X-linked hydrocephalus family.

    Coucke P, Vits L, Van Camp G, Serville F, Lyonnet S, Kenwrick S, Rosenthal A, Wehnert M, Munnich A and Willems PJ

    Department of Medical Genetics, University of Antwerp-UIA, Belgium.

    Human molecular genetics 1994;3;4;671-3

  • A duplication in the L1CAM gene associated with X-linked hydrocephalus.

    Van Camp G, Vits L, Coucke P, Lyonnet S, Schrander-Stumpel C, Darby J, Holden J, Munnich A and Willems PJ

    Department of Medical Genetics, University of Antwerp-UIA, Belgium.

    Recently, a mutation in the gene for the neural cell adhesion molecule L1CAM, located at chromosome Xq28, was found in a family with X-linked hydrocephalus (HSAS). However, as the L1CAM mutation could only be identified in one HSAS family, it remained unclear whether or not L1CAM was the gene responsible for HSAS. We have conducted a mutation analysis of L1CAM in 25 HSAS families. The mutation reported previously was not found in any of these families. In one family, however, a 1.3 kilobases (kb) genomic duplication was identified, cosegregating with HSAS and significantly changing the intracellular domain of the L1CAM protein. These results confirm that L1CAM is the HSAS gene.

    Nature genetics 1993;4;4;421-5

Pubmed - other

  • L1 cell adhesion molecule is a novel independent poor prognostic factor of extrahepatic cholangiocarcinoma.

    Li S, Jo YS, Lee JH, Min JK, Lee ES, Park T, Kim JM and Hong HJ

    Department of Pathology and Infection Signaling Network Research Center, Chungnam National University School of Medicine, Daejeon, Korea.

    Purpose: Cholangiocarcinomas (CC) are associated with poor survival, but diagnostic markers and therapeutic targets have not yet been elucidated. We previously found aberrant expression of L1 cell adhesion molecule in intrahepatic CC and a role for L1 in the progression of intrahepatic CC. Here, we analyzed L1 expression in extrahepatic CC (ECC) and evaluated its prognostic significance.

    We examined L1 expression in tumors from 75 ECC patients by immunohistochemistry. We analyzed the correlations between L1 expression and clinicopathologic factors as well as patient survival.

    Results: L1 was not expressed in normal extrahepatic bile duct epithelium but was aberrantly expressed in 42.7% of ECC tumors. High expression of L1 was detected at the invasive front of tumors and was significantly associated with perineural invasion (P < 0.01). Univariate analysis indicated that various prognostic factors such as histologic grade 3, advanced pathologic T stage and clinical stage, perineural invasion, nodal metastasis, and high expression of L1 were risk factors predicting patient survival. Multivariate analyses done by Cox's proportional hazards model showed that high expression of L1 (hazard ratio, 2.171; 95% confidence interval, 1.162-4.055; P = 0.015) and nodal metastasis (hazard ratio, 2.088; 95% confidence interval, 1.159-3.764; P = 0.014) were independent risk factors for patient death.

    Conclusions: L1 was highly expressed in 42.7% of ECC and its expression was significantly associated with perineural invasion. High expression of L1 and nodal metastasis were independent poor prognostic factors predicting overall survival in patients with ECC.

    Clinical cancer research : an official journal of the American Association for Cancer Research 2009;15;23;7345-51

  • Tyrosine and serine phosphorylation regulate the conformation and subsequent threonine phosphorylation of the L1 cytoplasmic domain.

    Chen MM, Leland HA, Lee CY and Silletti S

    Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093-0803, USA.

    Previously we identified threonine-1172 (T1172) in the cytoplasmic domain of the cell adhesion molecule L1 as phosphorylated in pancreatic cancer cells. Although both CKII- and PKC-blockade suppressed this modification, only CKII was capable of phosphorylating T1172 of a recombinant L1 cytoplasmic domain, suggesting the requirement for additional events to facilitate availability of T1172 to PKC. In this study, we demonstrate that the region around T1172 exists in distinct conformations based on both T1172 phosphorylation and the integrity of surrounding residues. We further demonstrate the role of membrane-proximal and membrane-distal residues in regulating cytoplasmic domain conformation, and that modification of 3 of the 4 tyrosines in the L1 cytoplasmic domain promote conformational changes that facilitate other events. In particular, phenylalanine-substitution of tyrosine-1151 or tyrosine-1229 promote opening up of the cytoplasmic domain in a manner that facilitates phosphorylation of the other 3 tyrosines, as well as phosphorylation of T1172 by PKCalpha. Importantly, we show that phosphorylation of serine-1181 is required for T1172 phosphorylation by CKII. These data define a specific role for secondary structure in regulating the availability of T1172 that facilitates phosphorylation by PKC.

    Funded by: NCI NIH HHS: CA109956, CA130104, R03 CA109956, R03 CA109956-02, R03 CA130104, R03 CA130104-02

    Biochemical and biophysical research communications 2009;389;2;257-64

  • Expression and prognostic value of L1-CAM in breast cancer.

    Schröder C, Schumacher U, Fogel M, Feuerhake F, Müller V, Wirtz RM, Altevogt P, Krenkel S, Jänicke F and Milde-Langosch K

    Department of Gynecology, University Medical Center Hamburg-Eppendorf, D-20246 Hamburg, Germany.

    The L1 adhesion molecule (L1-CAM) is associated with impaired prognosis in many carcinomas. However, limited information about its expression in breast cancer tissue is available. Therefore, we carried out an analysis on L1 expression in primary breast cancers using a combination of Western blot, DNA-microarray analysis and immunohistochemistry. We observed L1 protein and mRNA overexpression in 14-15% of the carcinomas and this was confirmed by immunohistochemical staining. High L1 expression was associated with nodal involvement, high grading, human epidermal growth receptor 2 (Her-2), plasminogen activator inhibitor 1 (PAI-1) and vascular endothelial growth factor (VEGF) expression and a negative estrogen receptor (ER) status, but not with neuroendocrine markers. Moreover, patients with tumors showing high L1-CAM expression had a shorter disease-free and overall survival. Given the emerging functional role of L1 in promoting tumor cell migration, invasion, tumor growth and metastasis, our results suggest that L1 may have this function in breast cancer as well.

    Oncology reports 2009;22;5;1109-17

  • Pathogenic human L1-CAM mutations reduce the adhesion-dependent activation of EGFR.

    Nagaraj K, Kristiansen LV, Skrzynski A, Castiella C, Garcia-Alonso L and Hortsch M

    Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, 48109-2200, USA.

    L1-cell adhesion molecule (L1-CAM) belongs to a functionally conserved group of neural cell adhesion molecules that are implicated in many aspects of nervous system development. In many neuronal cells the adhesive function of L1-type CAMs induces cellular signaling processes that involves the activation of neuronal tyrosine protein kinases and among other functions regulates axonal growth and guidance. Mutations in the human L1-CAM gene are responsible for a complex neurodevelopmental condition, generally referred to as L1 syndrome. Several pathogenic L1-CAM mutations have been identified in humans that cause L1 syndrome in affected individuals without affecting the level of L1-CAM-mediated homophilic cell adhesion when tested in vitro. In this study, an analysis of two different pathogenic human L1-CAM molecules indicates that although both induce normal L1-CAM-mediated cell aggregation, they are defective in stimulating human epidermal growth factor receptor tyrosine kinase activity in vitro and are unable to rescue L1 loss-of-function conditions in a Drosophila transgenic model in vivo. These results indicate that the L1 syndrome-associated phenotype might involve the disruption of L1-CAM's functions at different levels. Either by reducing or abolishing L1-CAM protein expression, by interfering with L1-CAM's cell surface expression, by reducing L1-CAM's adhesive ability or by impeding further downstream adhesion-dependent signaling processes.

    Funded by: NINDS NIH HHS: R01 NS32130

    Human molecular genetics 2009;18;20;3822-31

  • Identification of new putative susceptibility genes for several psychiatric disorders by association analysis of regulatory and non-synonymous SNPs of 306 genes involved in neurotransmission and neurodevelopment.

    Gratacòs M, Costas J, de Cid R, Bayés M, González JR, Baca-García E, de Diego Y, Fernández-Aranda F, Fernández-Piqueras J, Guitart M, Martín-Santos R, Martorell L, Menchón JM, Roca M, Sáiz-Ruiz J, Sanjuán J, Torrens M, Urretavizcaya M, Valero J, Vilella E, Estivill X, Carracedo A and Psychiatric Genetics Network Group

    CIBER en Epidemiología y Salud Pública (CIBERESP), Instituto de Salud Carlos III, Madrid, Spain.

    A fundamental difficulty in human genetics research is the identification of the spectrum of genetic variants that contribute to the susceptibility to common/complex disorders. We tested here the hypothesis that functional genetic variants may confer susceptibility to several related common disorders. We analyzed five main psychiatric diagnostic categories (substance-abuse, anxiety, eating, psychotic, and mood disorders) and two different control groups, representing a total of 3,214 samples, for 748 promoter and non-synonymous single nucleotide polymorphisms (SNPs) at 306 genes involved in neurotransmission and/or neurodevelopment. We identified strong associations to individual disorders, such as growth hormone releasing hormone (GHRH) with anxiety disorders, prolactin regulatory element (PREB) with eating disorders, ionotropic kainate glutamate receptor 5 (GRIK5) with bipolar disorder and several SNPs associated to several disorders, that may represent individual and related disease susceptibility factors. Remarkably, a functional SNP, rs945032, located in the promoter region of the bradykinin receptor B2 gene (BDKRB2) was associated to three disorders (panic disorder, substance abuse, and bipolar disorder), and two additional BDKRB2 SNPs to obsessive-compulsive disorder and major depression, providing evidence for common variants of susceptibility to several related psychiatric disorders. The association of BDKRB2 (odd ratios between 1.65 and 3.06) to several psychiatric disorders supports the view that a common genetic variant could confer susceptibility to clinically related phenotypes, and defines a new functional hint in the pathophysiology of psychiatric diseases.

    American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 2009;150B;6;808-16

  • DNA hypomethylation at the CpG island is involved in aberrant expression of the L1 cell adhesion molecule gene in colorectal cancer.

    Kato K, Maesawa C, Itabashi T, Fujisawa K, Otsuka K, Kanno S, Tada H, Tatemichi Y, Kotani K, Oikawa H, Sugai T, Wakabayashi G and Masuda T

    Department of Pathology, Iwate Medical University School of Medicine, 18-1 Uchimaru, Morioka, Japan.

    The L1 cell adhesion molecule (L1CAM) has been identified as a target gene of beta-catenin-TCF signaling in colorectal cancer (CRC) and associated with aggressive tumor behavior such as invasion and metastasis. We investigated the methylation status at the L1CAM gene promoter and/or L1CAM mRNA/protein expression in 4 CRC cell lines and 71 primary CRCs. Aberrant L1CAM expression was immuno histochemically observed in 31 (43.7%) of 71 cases, and correlated with advanced stage and presence of lymph node and distant metastases (P<0.05). Treatment with a demethylating agent induced L1CAM mRNA/protein expression in two cell lines lacking L1CAM expression. Bisulfite-modified genome sequencing suggested that DNA methylation status at core promoter and putative TCF-binding sites within the L1CAM promoter was correlated with L1CAM mRNA/protein expression in 4 CRC cell lines. Using the crypt isolation followed by bisulfite-modified genome sequencing and methylation-specific PCR methods, we confirmed that the DNA hypomethylation at core promoter and putative TCF-binding sites was well correlated with the aberrant L1CAM protein expression in primary CRC samples. These results suggest that DNA hypomethylation at the L1CAM CpG islands might induce L1CAM aberrant expression and contribute to the acquisition of aggressive tumor behavior in CRC.

    International journal of oncology 2009;35;3;467-76

  • L1CAM mutation in association with X-linked hydrocephalus and Hirschsprung's disease.

    Jackson SR, Guner YS, Woo R, Randolph LM, Ford H and Shin CE

    Department of Pediatric Surgery, Children's Hospital Los Angeles, Keck School of Medicine, University of Southern California, 4650 Sunset Boulevard, Mailstop #72, Los Angeles, CA 90027, USA.

    X-linked hydrocephalus (XLH) is characterized by increased intracranial ventricle size and head circumference secondary to aqueduct of Sylvius congenital stenosis. Exceedingly rare is the concurrence of XLH and Hirschsprung's disease (HSCR) with a theoretical incidence of 1 in 125-250 million cases. Herein, we are describing a case of a patient with concurrent XLH and HSCR. The patient was delivered via cesarean section at 37 weeks gestation and underwent uneventful ventriculoperitoneal shunt placement. As a part of a workup for constipation, we performed a rectal biopsy, which was consistent with HSCR. Genetics testing showed hemizygous for R558X hemizygous mutation in the L1CAM gene. A C --> T nucleotide substitution in exon 13 resulted in replacement of an arginine codon with a stop codon, a nonsense mutation. Although it is widely accepted that HSCR represents the failure of early embryonic neural crest cells to migrate properly, the exact mechanism is not known. The association of HSCR with XLH in the presence of L1CAM mutations remains quite interesting because cell adhesion molecules are involved in the proper migration of neural components throughout the body. Additional studies are necessary to fully elucidate the relationship between XLH and HSCR in the presence of L1CAM mutations.

    Pediatric surgery international 2009;25;9;823-5

  • The AA genotype of a L1C G842A polymorphism is associated with an increased risk for ovarian cancer.

    Heubner M, Wimberger P, Kasimir-Bauer S, Otterbach F, Kimmig R and Siffert W

    Institute of Pharmacogenetics, University of Duisburg-Essen, Hufelandstr. 55, 45147 Essen, Germany. Martin.heubner@uk-essen.de

    Background: Recent studies proposed L1CAM (L1 cell adhesion molecule) expression as a negative prognostic marker in epithelial ovarian cancer (EOC). The gene L1C was screened for single nucleotide polymorphisms (SNPs) which could impact upon EOC risk or disease progression.

    Overlapping DNA fragments, including the promoter region, intron 1 and all the exons of 10 healthy volunteers were analyzed to detect SNPs. EOC patients (n=103) and age-matched controls (n=104) were subsequently genotyped by restriction fragment length polymorphism (RFLP). Quantitative real-time PCR was carried out to detect potential associations of SNPs with L1C mRNA expression.

    Results: One SNP was found in intron 1 (L1C G842A). Genotyping of the EOC patients and age-matched controls revealed an association of EOC with the homozygous AA genotype (OR 7.4, CI 1.6-33.5; p=0.003). The L1C mRNA expression levels and clinical parameters did not differ significantly between the L1C G842A genotypes.

    Conclusion: The L1C 842 AA genotype may be a predisposing factor for EOC.

    Anticancer research 2009;29;8;3449-52

  • The soluble form of the cancer-associated L1 cell adhesion molecule is a pro-angiogenic factor.

    Friedli A, Fischer E, Novak-Hofer I, Cohrs S, Ballmer-Hofer K, Schubiger PA, Schibli R and Grünberg J

    Center for Radiopharmaceutical Science ETH-PSI-USZ, Paul Scherrer Institute, Villigen, Switzerland.

    A soluble form of the L1 cell adhesion molecule (sL1) is released from various tumor cells and can be found in serum and ascites fluid of uterine and ovarian carcinoma patients. sL1 is a ligand for several Arg-Gly-Asp (RGD)-binding integrins and can be deposited in the extracellular matrix. In this study we describe a novel function of this physiologically relevant form of L1 as a pro-angiogenic factor. We demonstrated that the anti-L1 monoclonal antibody (mAb) chCE7 binds near or to the sixth Ig-like domain of human L1 which contains a single RGD sequence. mAb chCE7 inhibited the RGD-dependent adhesion of ovarian carcinoma cells to sL1 and reversed the sL1-induced proliferation, matrigel invasion and tube formation of bovine aortic endothelial (BAE) cells. A combination of sL1 with vascular endothelial growth factor-A (VEGF-A(165)), which is an important angiogenic inducer in tumors, strongly potentiated VEGF receptor-2 tyrosine phosphorylation in BAE cells. Chick chorioallantoic membrane (CAM) assays revealed the pro-angiogenic potency of sL1 in vivo which could be abolished by chCE7. These results indicate an important role of released L1 in tumor angiogenesis and represent a novel function of antibody chCE7 in tumor therapy.

    The international journal of biochemistry & cell biology 2009;41;7;1572-80

  • Association study between single-nucleotide polymorphisms in 199 drug-related genes and commonly measured quantitative traits of 752 healthy Japanese subjects.

    Saito A, Kawamoto M and Kamatani N

    Division of Genomic Medicine, Department of Advanced Biomedical Engineering and Science, Tokyo Women's Medical University, Shinjuku-ku, Tokyo, Japan. a-saito@horae.dti.ne.jp

    With dense single-nucleotide polymorphism (SNP) maps for 199 drug-related genes, we examined associations between 4190 SNPs and 38 commonly measured quantitative traits using data from 752 healthy Japanese subjects. On analysis, we observed a strong association between five SNPs within the uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) gene and serum total bilirubin levels (minimum P-value in Mann-Whitney test=1.82 x 10(10)). UGT1A1 catalyzes the conjugation of bilirubin with glucuronic acid, thus enhancing bilirubin elimination. This enzyme is known to play an important role in the variation of serum bilirubin levels. The five SNPs, including a nonsynonymous SNP-rs4148323 (211G>A or G71R variant allele known as UGT1A1*6)-showed strong linkage disequilibrium with each other. No other genes were clearly associated with serum total bilirubin levels. Results of linear multiple regression analysis on serum total bilirubin levels followed by analysis of variance showed that at least 13% of the variance in serum total bilirubin levels could be explained by three haplotype-tagging SNPs in the UGT1A1 gene.

    Journal of human genetics 2009;54;6;317-23

  • Nuclear translocation and signalling of L1-CAM in human carcinoma cells requires ADAM10 and presenilin/gamma-secretase activity.

    Riedle S, Kiefel H, Gast D, Bondong S, Wolterink S, Gutwein P and Altevogt P

    Translational Immunology, German Cancer Research Center, Im Neuenheimer Feld 280, Heidelberg, Federal Republic of Germany.

    L1-CAM (L1 cell-adhesion molecule), or more simply L1, plays an important role in the progression of human carcinoma. Overexpression promotes tumour-cell invasion and motility, growth in nude mice and tumour metastasis. It is feasible that L1-dependent signalling contributes to these effects. However, little is known about its mechanism in tumour cells. We reported previously that L1 is cleaved by ADAM (a disintegrin and metalloprotease) and that the cytoplasmic part is essential for L1 function. Here we analysed more closely the role of proteolytic cleavage in L1-mediated nuclear signalling. Using OVMz carcinoma cells and L1-transfected cells as a model, we found that ADAM10-mediated cleavage of L1 proceeds in lipid raft and non-raft domains. The cleavage product, L1-32, is further processed by PS (presenilin)/gamma-secretase to release L1-ICD, an L1 intracellular domain of 28 kDa. Overexpression of dominant-negative PS1 or use of a specific gamma-secretase inhibitor leads to an accumulation of L1-32. Fluorescence and biochemical analysis revealed a nuclear localization for L1-ICD. Moreover, inhibition of ADAM10 and/or gamma-secretase blocks nuclear translocation of L1-ICD and L1-dependent gene regulation. Overexpression of recombinant L1-ICD mediates gene regulation in a similar manner to full-length L1. Our results establish for the first time that regulated proteolytic processing by ADAM10 and PS/gamma-secretase is essential for the nuclear signalling of L1 in human carcinoma cell lines.

    The Biochemical journal 2009;420;3;391-402

  • Up-regulation of L1CAM in pancreatic duct cells is transforming growth factor beta1- and slug-dependent: role in malignant transformation of pancreatic cancer.

    Geismann C, Morscheck M, Koch D, Bergmann F, Ungefroren H, Arlt A, Tsao MS, Bachem MG, Altevogt P, Sipos B, Fölsch UR, Schäfer H and Müerköster SS

    Clinic of Internal Medicine, Laboratory of Molecular Gastroenterology and Hepatology, UKSH-Campus Kiel, Kiel, Germany.

    Pancreatic ductal adenocarcinoma (PDAC) is thought to originate from ductal structures, exhibiting strong desmoplastic reaction with stromal pancreatic myofibroblasts (PMF), which are supposed to drive PDAC tumorigenesis. Previously, we observed high expression of the adhesion molecule L1CAM (CD171) in PDAC cells accounting for chemoresistance. Thus, this study aimed to investigate whether PMFs are involved in the induction of tumoral L1CAM and whether this contributes to malignant transformation of pancreatic ductal cells and PDAC tumorigenesis. Immunohistochemistry of tissues from chronic pancreatitis specimens revealed considerable L1CAM expression in ductal structures surrounded by dense fibrotic tissue, whereas no L1CAM staining was seen in normal pancreatic tissues. Using the human pancreatic duct cell line H6c7, we show that coculture with PMFs led to a transforming growth factor-beta1 (TGF-beta1)-dependent up-regulation of L1CAM expression. Similarly, L1CAM expression increased in monocultured H6c7 cells after administration of exogenous TGF-beta1. Both TGF-beta1- and PMF-induced L1CAM expression were independent of Smad proteins but required c-Jun NH(2)-terminal kinase activation leading to the induction of the transcription factor Slug. Moreover, Slug interacted with the L1CAM promoter, and its knockdown abrogated the TGF-beta1- and PMF-induced L1CAM expression. As a result of L1CAM expression, H6c7 cells acquired a chemoresistant and migratory phenotype. This mechanism of TGF-beta1-induced L1CAM expression and the resulting phenotype could be verified in the TGF-beta1-responsive PDAC cell lines Colo357 and Panc1. Our data provide new insights into the mechanisms of tumoral L1CAM induction and how PMFs contribute to malignant transformation of pancreatic duct cells early in PDAC tumorigenesis.

    Cancer research 2009;69;10;4517-26

  • Prefrontal cortex shotgun proteome analysis reveals altered calcium homeostasis and immune system imbalance in schizophrenia.

    Martins-de-Souza D, Gattaz WF, Schmitt A, Rewerts C, Maccarrone G, Dias-Neto E and Turck CW

    Laboratório de Neurociências, Instituto de Psiquiatria, Universidade de São Paulo, Rua. Dr. Ovidio Pires de Campos, no 785, Consolação, São Paulo, SP 05403-010, Brazil.

    Schizophrenia is a complex disease, likely to be caused by a combination of serial alterations in a number of genes and environmental factors. The dorsolateral prefrontal cortex (Brodmann's Area 46) is involved in schizophrenia and executes high-level functions such as working memory, differentiation of conflicting thoughts, determination of right and wrong concepts and attitudes, correct social behavior and personality expression. Global proteomic analysis of post-mortem dorsolateral prefrontal cortex samples from schizophrenia patients and non-schizophrenic individuals was performed using stable isotope labeling and shotgun proteomics. The analysis resulted in the identification of 1,261 proteins, 84 of which showed statistically significant differential expression, reinforcing previous data supporting the involvement of the immune system, calcium homeostasis, cytoskeleton assembly, and energy metabolism in schizophrenia. In addition a number of new potential markers were found that may contribute to the understanding of the pathogenesis of this complex disease.

    European archives of psychiatry and clinical neuroscience 2009;259;3;151-63

  • Subset of esophageal adenocarcinoma expresses adhesion molecule l1 in contrast to squamous cell carcinoma.

    Rawnaq T, Kleinhans H, Uto M, Schurr PG, Reichelt U, Cataldegirmen G, Gawad KA, Yekebas EF, Schachner M, Izbicki JR and Kaifi JT

    Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany. trawnaq@uke.de

    Background: Esophageal adenocarcinoma is currently the most rapidly increasing cancer in Western populations. L1 (CD171), a neural cell adhesion molecule, has an essential function in tumor progression and has been shown to be expressed in the proliferating cells of the intestinal crypts in mice. The aim of the current study was to determine L1 expression in esophageal cancer and to evaluate whether L1 could serve as a potential marker and therapeutic target for this tumor type.

    L1 expression was assessed on a tissue microarray with 257 surgically resected esophageal cancer samples by immunohistochemistry with a monoclonal antibody (Clone UJ127). L1 expression was correlated with clinicopathological data.

    Results: L1 was detected in 22 (9%) of 257 esophageal cases, whereas 235 (91%) were L1 negative. Nineteen (86%) of the 22 L1-positive cases were adenocarcinoma. Cross table analysis showed a significant association between L1 expression and adenocarcinoma subtype (p<0.001), but not squamous cell carcinoma.

    Conclusion: L1 expression in a subgroup of esophageal cancer is specifically prevalent in adenocarcinoma. Data suggest L1 as a potential target for biological therapy in L1-positive esophageal adenocarcinoma patients.

    Anticancer research 2009;29;4;1195-9

  • The adhesion molecule L1 regulates transendothelial migration and trafficking of dendritic cells.

    Maddaluno L, Verbrugge SE, Martinoli C, Matteoli G, Chiavelli A, Zeng Y, Williams ED, Rescigno M and Cavallaro U

    The FIRC Institute of Molecular Oncology, 20139 Milan, Italy.

    The adhesion molecule L1, which is extensively characterized in the nervous system, is also expressed in dendritic cells (DCs), but its function there has remained elusive. To address this issue, we ablated L1 expression in DCs of conditional knockout mice. L1-deficient DCs were impaired in adhesion to and transmigration through monolayers of either lymphatic or blood vessel endothelial cells, implicating L1 in transendothelial migration of DCs. In agreement with these findings, L1 was expressed in cutaneous DCs that migrated to draining lymph nodes, and its ablation reduced DC traf bfb ficking in vivo. Within the skin, L1 was found in Langerhans cells but not in dermal DCs, and L1 deficiency impaired Langerhans cell migration. Under inflammatory conditions, L1 also became expressed in vascular endothelium and enhanced transmigration of DCs, likely through L1 homophilic interactions. Our results implicate L1 in the regulation of DC trafficking and shed light on novel mechanisms underlying transendothelial migration of DCs. These observations might offer novel therapeutic perspectives for the treatment of certain immunological disorders.

    Funded by: Telethon: GGP04078

    The Journal of experimental medicine 2009;206;3;623-35

  • The clinical variability of the MECP2 duplication syndrome: description of two families with duplications excluding L1CAM and FLNA.

    Kirk EP, Malaty-Brevaud V, Martini N, Lacoste C, Levy N, Maclean K, Davies L, Philip N and Badens C

    Clinical genetics 2009;75;3;301-3

  • Enhanced L1CAM expression on pancreatic tumor endothelium mediates selective tumor cell transmigration.

    Issa Y, Nummer D, Seibel T, Müerköster SS, Koch M, Schmitz-Winnenthal FH, Galindo L, Weitz J, Beckhove P and Altevogt P

    Tumor Immunology Programme, D015, German Cancer Research Center, Im Neuenheimer Feld 280, 69120, Heidelberg, Germany.

    L1 cell adhesion molecule (L1CAM) is a transmembrane cell adhesion molecule initially defined as a promigratory molecule in the developing nervous system that appears to be also expressed in some endothelial cells. However, little is known about the functional role of L1CAM on endothelial cells. We observed that L1CAM expression was selectively enhanced on endothelium associated with pancreatic adenocarcinoma in situ and on cultured pancreatic tumor-derived endothelial cells in vitro. L1CAM expression of endothelial cells could be augmented by incubation with immunomodulatory cytokines such as tumor necrosis factor alpha, interferon gamma, or transforming growth factor beta 1. Antibodies to L1CAM and the respective ligand neuropilin-1 blocked tube formation and stromal cell-derived factor 1beta induced transmigration of tumor endothelial cells in vitro. L1CAM expression on tumor-derived-endothelial cells enhanced Panc1 carcinoma cell adhesion to endothelial cell monolayers and transendothelial migration. Our data demonstrate a functional role of L1CAM expression on tumor endothelium that could favor metastasis and angiogenesis during tumor progression.

    Journal of molecular medicine (Berlin, Germany) 2009;87;1;99-112

  • Universal expression of cell adhesion molecule NCAM in neuroblastoma in contrast to L1: implications for different roles in tumor biology of neuroblastoma?

    Wachowiak R, Rawnaq T, Metzger R, Quaas A, Fiegel H, Kähler N, Rolle U, Izbicki JR, Kaifi J and Till H

    Department of Pediatric Surgery, University of Leipzig, Liebigstrasse 20A, 04103, Leipzig, Germany. robin.wachowiak@medizin.uni-leipzig.de

    Purpose: Neuroblastoma is a biological, genetic and morphological heterogeneous tumor with a variable clinical course. NCAM is a cell adhesion molecule belonging to the immunoglobulin superfamily with structural similarities to cell adhesion molecule L1. The aim of this study was to determine the expression of NCAM in neuroblastoma and to compare the results to the findings of a previous study which examined L1 expression in the same group of patients.

    NCAM expression was investigated on a tissue array with 66 surgically resected neuroblastoma samples by immunohistochemistry with a monoclonal antibody clone 1B6 and peroxidase method.

    Results: Strong expression of NCAM was detected in all of the 66 (100%) neuroblastoma tumors in contrast to L1 which was not expressed in all tumors.

    Conclusion: In contrast to L1, which was found to predict favorable outcome, NCAM is universally expressed in neuroblastoma. Therefore NCAM represents a marker for neuroblastomas irrespectively of their stages whereas L1 as an indicator for developing neuronal cells seems to identify more mature stages of this tumor. The high grade of NCAM expression might present a prerequisite for establishment of antibody-based therapies.

    Pediatric surgery international 2008;24;12;1361-4

  • L1-CAM in cancerous tissues.

    Gavert N, Ben-Shmuel A, Raveh S and Ben-Ze'ev A

    Weizmann Institute of Science, Department of Molecular Cell Biology, Rehovot, Israel.

    Background: L1-cell adhesion molecule (L1-CAM) is a cell adhesion receptor of the immunoglobulin superfamily, known for its roles in nerve cell function. While originally believed to be present only in brain cells, in recent years L1-CAM has been detected in other tissues, and in a variety of cancer cells, including some common types of human cancer.

    We review the prevalence of L1-CAM in human cancer, the possible mechanisms involved in L1-CAM-mediated tumorigenesis, and cancer therapies based upon L1-CAM antibody treatment.

    In colon cancer cells, the L1-CAM gene was identified as a target of the Wnt/beta-catenin-TCF signaling pathway, and L1-CAM was exclusively detected at the invasive front of colon and ovarian cancer tissue. The expression of L1-CAM in normal and cancer cells enhanced tumorigenesis and conferred metastasis in colon cancer cells. Antibodies against the L1-CAM ectodomain severely inhibited the proliferation of a variety of cancer cells in culture and reduced tumor burden when injected into mice harboring cancer cells expressing L1-CAM. These results, in addition to the presence of L1-CAM on the cell surface and its restricted distribution in normal tissues, make it an ideal target for tumor therapy.

    Expert opinion on biological therapy 2008;8;11;1749-57

  • Kinetic analysis of L1 homophilic interaction: role of the first four immunoglobulin domains and implications on binding mechanism.

    Gouveia RM, Gomes CM, Sousa M, Alves PM and Costa J

    Instituto de Tecnologia Química e Biológica, Avenida da República, Apartado 127, 2780-157 Oeiras, Portugal.

    L1 is a cell adhesion molecule of the immunoglobulin (Ig) superfamily, critical for central nervous system development, and involved in several neuronal biological events. It is a type I membrane glycoprotein. The L1 ectodomain, composed of six Ig-like and five fibronectin (Fn) type-III domains, is involved in homophilic binding. Here, co-immunoprecipitation studies between recombinant truncated forms of human L1 expressed and purified from insect Spodoptera frugiperda Sf9 cells, and endogenous full-length L1 from human NT2N neurons, showed that the L1 ectodomain (L1/ECD) and L1/Ig1-4 interacted homophilically in trans, contrary to mutants L1/Ig1-3 and L1/Ig2-Fn5. All mutants were correctly folded as evaluated by combination of far-UV CD and fluorescence spectroscopy. Surface plasmon resonance analysis showed comparable dissociation constants of 116 +/- 2 and 130 +/- 6 nm for L1/ECD-L1/ECD and L1/ECD-L1/Ig1-4, respectively, whereas deletion mutants for Ig1 or Ig4 did not interact. Accordingly, in vivo, Sf9 cells stably expressing L1 were found to adhere only to L1/ECD- and L1/Ig1-4-coated surfaces. Furthermore, only these mutants bound to HEK293 cells overexpressing L1 at the cell surface. Enhancement of neurite outgrowth, which is the consequence of signaling events caused by L1 homophilic binding, was comparable between L1/ECD and L1/Ig1-4. Altogether, these results showed that domains Ig1 to Ig4 are necessary and sufficient for L1 homophilic binding in trans, and that the rest of the molecule does not contribute to the affinity under the conditions of the current study. Furthermore, they are compatible with a cooperative interaction between modules Ig1-Ig4 in a horseshoe conformation.

    The Journal of biological chemistry 2008;283;42;28038-47

  • Targeting cancer stem cells through L1CAM suppresses glioma growth.

    Bao S, Wu Q, Li Z, Sathornsumetee S, Wang H, McLendon RE, Hjelmeland AB and Rich JN

    Department of Surgery, Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, North Carolina 27710, USA. shideng.bao@uchsc.edu

    Malignant gliomas are lethal cancers that display striking cellular heterogeneity. A highly tumorigenic glioma tumor subpopulation, termed cancer stem cells or tumor-initiating cells, promotes therapeutic resistance and tumor angiogenesis. Therefore, targeting cancer stem cells may improve patient survival. We interrogated the role of a neuronal cell adhesion molecule, L1CAM, in glioma stem cells as L1CAM regulates brain development and is expressed in gliomas. L1CAM(+) and CD133(+) cells cosegregated in gliomas, and levels of L1CAM were higher in CD133(+) glioma cells than normal neural progenitors. Targeting L1CAM using lentiviral-mediated short hairpin RNA (shRNA) interference in CD133(+) glioma cells potently disrupted neurosphere formation, induced apoptosis, and inhibited growth specifically in glioma stem cells. We identified a novel mechanism for L1CAM regulation of cell survival as L1CAM knockdown decreased expression of the basic helix-loop-helix transcription factor Olig2 and up-regulated the p21(WAF1/CIP1) tumor suppressor in CD133(+) glioma cells. To determine if targeting L1CAM was sufficient to reduce glioma stem cell tumor growth in vivo, we targeted L1CAM in glioma cells before injection into immunocompromised mice or directly in established tumors. In each glioma xenograft model, shRNA targeting of L1CAM expression in vivo suppressed tumor growth and increased the survival of tumor-bearing animals. Together, these data show that L1CAM is required for maintaining the growth and survival of CD133(+) glioma cells both in vitro and in vivo, and L1CAM may represent a cancer stem cell-specific therapeutic target for improving the treatment of malignant gliomas and other brain tumors.

    Funded by: NCI NIH HHS: CA116659, CA116659-03, CA129958, CA129958-01A1, R01 CA116659, R01 CA116659-03, R01 CA129958, R01 CA129958-01A1; NINDS NIH HHS: K02 NS047409, K02 NS047409-04, NS047409, NS047409-04, NS054276, NS054276-03, R01 NS054276, R01 NS054276-03

    Cancer research 2008;68;15;6043-8

  • The RGD integrin binding site in human L1-CAM is important for nuclear signaling.

    Gast D, Riedle S, Kiefel H, Müerköster SS, Schäfer H, Schäfer MK and Altevogt P

    Tumor Immunology Programme, D010, German Cancer Research Center, Heidelberg, Germany.

    L1 cell adhesion molecule (L1-CAM) is a transmembrane cell adhesion molecule initially defined as a promigratory molecule in the developing nervous system. L1 is also overexpressed in a variety of human carcinomas and is associated with bad prognosis. In carcinoma cell lines L1 augments cell motility and metastasis, tumor growth in nude mice and induces expression of L1-dependent genes. It is not known whether L1-signaling requires ligand binding. The RGD motif in the sixth Ig domain of L1 is a binding site for integrins. In the present study we analyzed the role of RGDs in L1-signaling using site-directed mutagenesis combined with antibody blocking studies. We observed that L1-RGE expressing HEK293 cells showed reduced cell-cell binding, cell motility, invasiveness and tumor growth in NOD/SCID mice. The RGE-mutation impaired L1-dependent gene regulation and antibodies to alphavbeta5 integrin had similar effects. Mutant L1 was unable to translocate to the nucleus. Our findings highlight the importance of the RGD site in L1 for human tumors and suggest that nuclear signaling of L1 is dependent on integrins.

    Experimental cell research 2008;314;13;2411-8

  • Attenuation of melanoma invasion by a secreted variant of activated leukocyte cell adhesion molecule.

    van Kilsdonk JW, Wilting RH, Bergers M, van Muijen GN, Schalkwijk J, van Kempen LC and Swart GW

    Department of Biomolecular Chemistry 271, Institute for Molecules and Materials and Nijmegen Centre for Molecular Life Sciences, Faculty of Science, Radboud University Nijmegen.

    Activated leukocyte cell adhesion molecule (ALCAM/CD166/MEMD), a marker of various cancers and mesenchymal stem cells, is involved in melanoma metastasis. We have exploited a secreted NH(2)-terminal fragment, sALCAM, to test the hypothesis that ALCAM coordinates tissue growth and cell migration. Overexpression of sALCAM in metastatic melanoma cells disturbed clustering of endogenous ALCAM and inhibited activation of matrix metalloproteinase-2 (MMP-2). Exposure of HT1080 fibrosarcoma cells to sALCAM similarly inhibited MMP-2, suggesting a broader effect on ALCAM-positive tumor cells. In contrast to the previously reported, promotive effects of an NH(2)-terminally truncated, transmembrane variant (DeltaN-ALCAM), sALCAM impaired the migratory capacity of transfected cells in vitro, reduced basement membrane penetration in reconstituted human skin equivalents, and diminished metastatic capacity in nude mice. Remarkably, L1 neuronal cell adhesion molecule (L1CAM/CD171), another progression marker of several cancers including melanoma, was suppressed upon sALCAM overexpression but was up-regulated by DeltaN-ALCAM. The partially overlapping and opposite effects induced by alternative strategies targeting ALCAM functions collectively attribute an integrative role to ALCAM in orchestrating cell adhesion, growth, invasion, and proteolysis in the tumor tissue microenvironment and disclose a therapeutic potential for sALCAM.

    Cancer research 2008;68;10;3671-9

  • L1 cell adhesion molecule (L1CAM) as a pathogenetic factor in endometriosis.

    Finas D, Huszar M, Agic A, Dogan S, Kiefel H, Riedle S, Gast D, Marcovich R, Noack F, Altevogt P, Fogel M and Hornung D

    Department of Obstetrics and Gynecology, University of Schleswig-Holstein, Ratzeburgerallee 160, 23538 Luebeck, Germany.

    Background: Endometriosis is a benign and progressive disease with a high prevalence. Women with endometriosis, especially with atypical endometriosis, have a higher probability for developing ovarian cancer compared with women without endometriosis. The L1 cell adhesion molecule (L1CAM) is over expressed in ovarian and endometrial carcinomas and is associated with a bad prognosis. Here, we have analysed L1CAM expression in endometriosis.

    In our study with the samples from 79 patients with, and 37 patients without, endometriosis, we found that endometriosis cell lines and short-term cultures of endometrium from women with endometriosis expressed L1CAM at the mRNA and protein level. Quantitative RT-PCR analysis showed that L1CAM was expressed at significantly higher level in the epithelial compartment from patients with endometriosis compared with healthy controls (P = 0.0126). By immunohistochemical staining, 15 of 31 ovarian endometriotic lesions (48%) were shown to have L1CAM-positive staining. Of these 15 L1CAM-positive samples, 13 were atypical endometriotic lesions. Soluble L1 present in the conditioned medium of epithelial endometrium cultures from women with endometriosis was able to stimulate neurite outgrowth as measured in a chicken ganglion assay.

    Conclusions: We propose that L1CAM could promote endometriosis development by increasing enervation and aggravation. L1CAM expression is higher in atypical endometriosis compared with normal endometriosis.

    Human reproduction (Oxford, England) 2008;23;5;1053-62

  • The L1 cell adhesion molecule is a potential biomarker of human distal nephron injury in acute tubular necrosis.

    Allory Y, Audard V, Fontanges P, Ronco P and Debiec H

    INSERM UMR S 702, Paris, France.

    The L1 cell adhesion molecule (CD171) is a multidomain membrane glycoprotein of the immunoglobulin superfamily. We evaluated its expression in human acute kidney injury and assessed its use as a tissue and urinary marker of acute tubular injury. Using immunohistochemical studies with antibodies to the extracellular or cytoplasmic domains, we compared L1 expression in normal kidneys in 24 biopsies taken from patients with acute tubular necrosis. L1 was found at the basolateral and the lateral membrane in all epithelial cells of the collecting duct in the normal kidney except for intercalated cells. In acute tubular necrosis, L1 lost its polarized distribution being found in both the basolateral and apical domains of the collecting duct. Further, it was induced in thick ascending limb and distal tubule cells. Apically expressed L1 found only when the cytoplasmic domain antibody was used in biopsy specimens of patients with acute tubular necrosis. The levels of urinary L1, normalized for creatinine, were significantly higher in all 24 patients with acute tubular necrosis compared to five patients with prerenal azotemia or to six patients with other causes of acute kidney injury. Our study shows that a soluble form of human L1 can be detected in the urine of patients with acute tubular necrosis and that this may be a marker of distal nephron injury.

    Kidney international 2008;73;6;751-8

  • The cytoplasmic part of L1-CAM controls growth and gene expression in human tumors that is reversed by therapeutic antibodies.

    Gast D, Riedle S, Issa Y, Pfeifer M, Beckhove P, Sanderson MP, Arlt M, Moldenhauer G, Fogel M, Krüger A and Altevogt P

    Tumor Immunology Programme, German Cancer Research Center, Heidelberg, Germany.

    L1 cell adhesion molecule (L1-CAM) is a transmembrane cell adhesion molecule involved in cell migration and axon guidance in the developing nervous system. L1 is also overexpressed in ovarian and endometrial carcinomas and is associated with a bad prognosis. In carcinoma cell lines, L1 overexpression augments cell motility, tumor growth in mice and induces expression of Erk-dependent genes. Here, we show that a mutation in the cytoplasmic portion of L1 (T1247A, S1248A) abrogates Erk activation, blocks cell migration on extracellular matrix proteins and did not augment tumor growth in non-obese diabetic/severe combined immuno-deficient mice. In cells expressing mutant L1, the induction of Erk-dependent genes such as beta3-integrin, cathepsin-B and several transcription factors is eliminated and the invasive phenotype is abrogated. L1 antibodies showed similar effects. They prevented Erk activation and interfered with the Erk-dependent gene expression pattern. These findings provide a rationale for the mode of action of L1 antibodies and suggest that interference with L1 function could become a valuable target for therapy.

    Oncogene 2008;27;9;1281-9

  • L1 (CAM) (CD171) in ovarian serous neoplasms.

    Daponte A, Kostopoulou E, Kollia P, Papamichali R, Vanakara P, Hadjichristodoulou C, Nakou M, Samara S, Koukoulis G and Messinis IE

    Department of Obstetrics & Gynecology, University Hospital of Larissa, Larissa, Greece. dapontea@otenet.gr

    The evaluation of L1 (CAM) as a tumor progression marker and as a prognostic factor in serous ovarian tumors.

    Methods: L1 (CAM) protein expression was assessed by immunohistochemistry and Western blot in serous ovarian tumors [cystadenomas (n = 20), borderline tumors (n = 14) and carcinomas (n = 47)], and was correlated with stage,grade, progression-free survival time (PFS) and overall survival.

    Results: L1 (CAM) immunoreactivity correlated significantly with stage and grade. It increased from benign tumors to early carcinomas and to advanced stage carcinomas progressively and significantly. In Stage III G3 carcinoma patients, low L1 (CAM) expressing tumors exhibited better response to chemotherapy and were associated with statistically significantly longer PFS (p = 0.002).

    Conclusion: L1 (CAM) expression represents a novel diagnostic marker in serous ovarian neoplasms that shows characteristics of tumor progression. L1 expression was associated with chemotherapy response.

    European journal of gynaecological oncology 2008;29;1;26-30

  • The role of adhesion molecules, alpha v beta 3, alpha v beta 5 and their ligands in the tumor cell and endothelial cell adhesion.

    Niu JX, Zhang WJ, Ye LY, Wu LQ, Zhu GJ, Yang ZH, Grau GE and Lou JN

    Institute of Basic Medical Sciences, Peking Union Medical College, Beijing, PR China.

    Tumor metastasis is a complex process involving the interaction between tumor cells and endothelial cells in which some adhesion molecules play an important role. It was our aim to investigate the role of the adhesion molecules, alpha v beta 3 and alpha v beta 5 and their ligands, developmental endothelial locus-1 (Del-1) and L1, in tumor cell adhesion to endothelial cells in vitro. In this study, the expression and regulation of alpha v beta 3, alpha v beta 5 and intercellular adhesion molecule -1 on liver sinusoidal endothelial cells and liver cancer endothelial cells (T3A) were analyzed by real-time PCR and fluorescent-activated cell sorter. The expression and regulation of the integrin ligands, Del-1 and L1, in six tumor cell lines were analyzed by real-time PCR and western blot. We found the expressions of alpha v beta 3 and alpha v beta 5 were higher on T3A than that on liver sinusoidal endothelial cells, whereas expression of intercellular adhesion molecule-1 was lower on T3A than that on liver sinusoidal endothelial cells. After 24 h hypoxia, the expressions of alpha v beta 3 and alpha v beta 5 were upregulated on T3A and liver sinusoidal endothelial cells; the expression of intercellular adhesion molecule-1 was increased on liver sinusoidal endothelial cells, but remained unchanged on T3A. Del-1 and L1 expression levels were obviously diverse in various tumor cell lines and differentially modulated after 12 h hypoxia. The adhesion of tumor cells with Del-1 and L1 expression was higher in T3A than that in liver sinusoidal endothelial cells, and was significantly increased under hypoxic conditions. Interestingly, the tumor cell adherence could be inhibited by antibodies against alpha v beta 5 and alpha v beta 5, but not by an antibody against intercellular adhesion molecule-1. The adhesion of tumor cells without Del-1 and L1 expression was also higher on T3A than that on liver sinusoidal endothelial cells, but the adhesion could not be inhibited by antibodies against alpha v beta 5, alpha v beta 5 or intercellular adhesion molecule-1, suggesting that other receptors are involved. In conclusion, alpha v beta 5, alpha v beta 5 and their ligands Del-1 and L1 play an important role in the process of tumor cells moving from the original place.

    European journal of cancer prevention : the official journal of the European Cancer Prevention Organisation (ECP) 2007;16;6;517-27

  • L1 is associated with micrometastatic spread and poor outcome in colorectal cancer.

    Kaifi JT, Reichelt U, Quaas A, Schurr PG, Wachowiak R, Yekebas EF, Strate T, Schneider C, Pantel K, Schachner M, Sauter G and Izbicki JR

    Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. jkaifi@uke.uni-hamburg.de

    L1 is a cell adhesion molecule expressed at the invasive front of colorectal tumors with an important role in metastasis. The aim of the present study was to determine L1 protein expression in a large cohort of colorectal cancer patients and its impact on early metastatic spread and survival. A total of 375 patients that underwent surgical treatment for colorectal cancer were chosen retrospectively. A tissue microarray was constructed of 576 tissue samples from these patients and analyzed by immunohistochemistry with a monoclonal antibody against human L1 (UJ127). Lymph node and bone marrow micrometastasis were assessed with monoclonal antibodies Ber-EP4 and pancytokeratin A45-B/B3, respectively. Associations between L1 expression and lymph node, bone marrow micrometastasis and survival were investigated with Fisher's, log-rank test and Cox multivariate analysis. All statistical tests were two-sided. L1 was detected in a subset of 48 (13%) of 375 patients examined. Analysis of L1 expression and survival revealed a significantly worse outcome for L1-positive patients by log-rank test (P<0.05). Multivariate Cox regression analysis showed the strongest independent prognostic impact of L1 expression (P<0.05). Fisher's test revealed a significant association of L1 expression and presence of disseminated tumor cells in lymph nodes and bone marrow (P<0.05). L1 is a powerful prognostic marker for patients that undergo complete surgical resection. It may have a role in early metastatic spread, as L1 is associated with micrometastases to both the lymph nodes and bone marrow. Thus, L1 should be explored further as a target for adjuvant therapy for micrometastatic disease.

    Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 2007;20;11;1183-90

  • The role of hereditary spastic paraplegia related genes in multiple sclerosis. A study of disease susceptibility and clinical outcome.

    DeLuca GC, Ramagopalan SV, Cader MZ, Dyment DA, Herrera BM, Orton S, Degenhardt A, Pugliatti M, Sadovnick AD, Sotgiu S and Ebers GC

    University Dept. of Clinical Neurology, University of Oxford, Radcliffe Infirmary, Woodstock Rd, Oxford, OX2 6LE, UK.

    Multiple sclerosis (MS) is a common inflammatory disease of the central nervous system unsurpassed for its variability in disease outcome. It has been observed that axonal loss in MS is significant and that irreversible clinical disability relates to such axonal loss. The clinical similarities between Hereditary Spastic Paraplegia (HSP) and progressive MS, along with their analogous profiles of axonal loss in the long tracts, make the genes known to cause HSP biologically relevant candidates for the study of clinical outcome in MS. A cohort of sporadic MS cases and a set of unaffected controls were used to determine the role of HSP genes on MS susceptibility and disease severity. The MS cases were taken from opposite extremes of the putative distribution of long-term outcome using the most stringent clinical criteria to date. Genotyping the two sets of MS patients and controls could not provide any evidence to suggest that genes involved in the pathogenesis of HSP (Paraplegin, NIPA1, KIF5A, HSPD1, Atlastin, Spartin, Spastin, PLP1, L1CAM, Maspardin and BSCL2) play a role in susceptibility to, or modifying the course of, MS, although small effects of these genes cannot be ruled out.

    Journal of neurology 2007;254;9;1221-6

  • Expression of L1-CAM and ADAM10 in human colon cancer cells induces metastasis.

    Gavert N, Sheffer M, Raveh S, Spaderna S, Shtutman M, Brabletz T, Barany F, Paty P, Notterman D, Domany E and Ben-Ze'ev A

    Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel.

    L1-CAM, a neuronal cell adhesion receptor, is also expressed in a variety of cancer cells. Recent studies identified L1-CAM as a target gene of beta-catenin-T-cell factor (TCF) signaling expressed at the invasive front of human colon cancer tissue. We found that L1-CAM expression in colon cancer cells lacking L1-CAM confers metastatic capacity, and mice injected in their spleen with such cells form liver metastases. We identified ADAM10, a metalloproteinase that cleaves the L1-CAM extracellular domain, as a novel target gene of beta-catenin-TCF signaling. ADAM10 overexpression in colon cancer cells displaying endogenous L1-CAM enhanced L1-CAM cleavage and induced liver metastasis, and ADAM10 also enhanced metastasis in colon cancer cells stably transfected with L1-CAM. DNA microarray analysis of genes induced by L1-CAM in colon cancer cells identified a cluster of genes also elevated in a large set of human colon carcinoma tissue samples. Expression of these genes in normal colon epithelium was low. These results indicate that there is a gene program induced by L1-CAM in colon cancer cells that is also present in colorectal cancer tissue and suggest that L1-CAM can serve as target for colon cancer therapy.

    Funded by: NCI NIH HHS: 5 P01 CA 565930-06

    Cancer research 2007;67;16;7703-12

  • L1 expression as a marker for poor prognosis, tumor progression, and short survival in patients with colorectal cancer.

    Boo YJ, Park JM, Kim J, Chae YS, Min BW, Um JW and Moon HY

    Department of Surgery, Korea University College of Medicine, Seoul, Korea.

    Background: L1, a new target gene for Wnt/beta-catenin-TCF signaling, has been identified in the invasive front of colorectal cancer cells in vitro study. The L1 molecule is localized on the cell surface in tumor tissues, accompanied with loss of beta-catenin and E-cadherin. However, such association between L1 expression and prognosis of colorectal cancer has not yet been investigated in clinical study. We investigated the expression of L1, E-cadherin, and beta-catenin in tumor cells to determine correlations between the clinicopathologic characteristics and the expression of these molecules and to evaluate the efficacy of the use of these molecules as prognostic markers for patient survival.

    Methods: We investigated 138 patients who received diagnoses of colorectal cancer and who underwent surgery between January 1995 and December 2000 at the Korea University Hospital. Tissues were obtained from paraffin-embedded blocks of the tumors and studied by tissue microarray analysis. Immunohistochemical staining for L1, beta-catenin, and E-cadherin was performed for each specimen.

    Results: L1 expression was found to be correlated with advanced cancer stage (P = .001), distant metastasis (P < .001), and tumor recurrence (P = .006). Survival analysis showed that reduced expression of beta-catenin and E-cadherin, and expression of L1 were statistically significantly related to poor survival. Multivariate analysis revealed that L1 expression was an independent prognostic factor for patient survival.

    Conclusions: L1 expression is associated with tumor progression and poor survival in patients with colorectal cancer and may be clinically useful as a marker for poor prognosis.

    Annals of surgical oncology 2007;14;5;1703-11

  • Two novel epilepsy-linked mutations leading to a loss of function of LGI1.

    Chabrol E, Popescu C, Gourfinkel-An I, Trouillard O, Depienne C, Senechal K, Baulac M, LeGuern E and Baulac S

    INSERM UMR 679, Neurologie and Thérapeutique Expérimentale, Université Pierre et Marie Curie-Paris 6, Faculté de Médecine, Assistance Publique-Hôpitaux de Paris, Hôpital de la Pitié-Salpêtrière, 47 boulevard de l'hôpital, 75013 Paris, France.

    Background: Mutations in the leucine-rich, glioma-inactivated 1 (LGI1) gene have been implicated in autosomal dominant lateral temporal epilepsy.

    Objective: To describe the clinical and genetic findings in 2 families with autosomal dominant lateral temporal epilepsy and the functional consequences of 2 novel mutations in LGI1.

    Design: Clinical, genetic, and functional investigations.

    Setting: University hospital. Patients Two French families with autosomal dominant lateral temporal epilepsy. Main Outcome Measure Mutation analysis.

    Results: Two novel disease-linked mutations, p.Leu232Pro and c.431 + 1G>A, were identified in LGI1. We demonstrated that the c.431 + 1G>A mutation causes the deletion of exons 3 and 4 of the LGI1 transcript and showed that the p.Leu232Pro mutation dramatically decreases secretion of the mutant protein by mammalian cells.

    Conclusion: Our data indicate that LGI1 is a secreted protein and suggest that LGI1-related epilepsy results from a loss of function.

    Archives of neurology 2007;64;2;217-22

  • Global, in vivo, and site-specific phosphorylation dynamics in signaling networks.

    Olsen JV, Blagoev B, Gnad F, Macek B, Kumar C, Mortensen P and Mann M

    Center for Experimental BioInformatics, Department of Biochemistry and Molecular Biology, University of Southern Denmark, DK-5230 Odense, Denmark.

    Cell signaling mechanisms often transmit information via posttranslational protein modifications, most importantly reversible protein phosphorylation. Here we develop and apply a general mass spectrometric technology for identification and quantitation of phosphorylation sites as a function of stimulus, time, and subcellular location. We have detected 6,600 phosphorylation sites on 2,244 proteins and have determined their temporal dynamics after stimulating HeLa cells with epidermal growth factor (EGF) and recorded them in the Phosida database. Fourteen percent of phosphorylation sites are modulated at least 2-fold by EGF, and these were classified by their temporal profiles. Surprisingly, a majority of proteins contain multiple phosphorylation sites showing different kinetics, suggesting that they serve as platforms for integrating signals. In addition to protein kinase cascades, the targets of reversible phosphorylation include ubiquitin ligases, guanine nucleotide exchange factors, and at least 46 different transcriptional regulators. The dynamic phosphoproteome provides a missing link in a global, integrative view of cellular regulation.

    Cell 2006;127;3;635-48

  • Molecular mechanisms and neuroimaging criteria for severe L1 syndrome with X-linked hydrocephalus.

    Kanemura Y, Okamoto N, Sakamoto H, Shofuda T, Kamiguchi H and Yamasaki M

    Institute for Clinical Research and Department of Neurosurgery, Osaka National Hospital, Osaka, Japan.

    Object: Mutations in the gene that codes for the human neural cell adhesion molecule L1 (L1CAM), are known to cause a wide variety of anomalies, now understood as phenotypic expressions of L1 syndrome. The correlations between genotype and phenotype, however, are not fully established. The authors report the results of a nationwide investigation of L1CAM gene mutations that was performed to improve the understanding of L1-mediated molecular mechanisms of X-linked hydrocephalus and to establish neurorimaging criteria for this severe form of L1 syndrome.

    Methods: Ninety-six genomic DNA samples from members of 57 families were obtained from the Congenital Hydrocephalus Research Committee. By using polymerase chain reaction and direct DNA sequencing, the authors identified 25 different L1CAM gene mutations, 20 of them novel, in 26 families with X-linked hydrocephalus. All the mutations were L1CAM loss-of-function mutations, and all the patients had severe hydrocephalus and severe mental retardation. In all cases, specific abnormalities were visible on neuroimaging: a rippled ventricular wall after shunt placement, an enlarged quadrigeminal plate, a large massa intermedia, and hypoplasia of the cerebellar vermis (anterior or total). The patients also had adducted thumbs, spastic paraplegia, and hypoplasia of the corpus callosum, which are characteristic of L1 syndrome.

    Conclusions: The L1CAM loss-of-function mutations cause a severe form of L1 syndrome, unlike the milder form produced by mutations in the L1CAM cytoplasmic domain. We also identified neurorimaging criteria for this severe form of L1 syndrome. These criteria can be used to predict loss-of-function mutations in patients with X-linked hydrocephalus and to help in diagnosing this syndrome.

    Journal of neurosurgery 2006;105;5 Suppl;403-12

  • The adhesion molecule L1 (CD171) promotes melanoma progression.

    Meier F, Busch S, Gast D, Göppert A, Altevogt P, Maczey E, Riedle S, Garbe C and Schittek B

    Department of Dermatology, Section of Dermatologic Oncology, University of Tuebingen, Tuebingen, and Tumor Immunology Programme, German Cancer Research Center, Heidelberg, Germany. friedegund.meier@med.uni-tuebingen.de

    The adhesion molecule L1 is expressed in primary melanomas and cutaneous metastases in contrast to melanocytic nevi and melanocytes, and is significantly associated with metastatic spread. Recent studies have demonstrated that in carcinomas L1 expression is associated with sustained activation of the extracellular signal-regulated kinase (ERK) pathway and upregulation of ERK-dependent, motility- and invasion-associated gene products including alphavbeta3 integrin. The objective of this study was to further investigate the role of the adhesion molecule L1 in melanoma progression, and to evaluate whether targeting the L1 adhesion molecule would have therapeutic effects against invasive melanoma growth. Using human melanoma cells from different stages of progression in monolayer and organotypic human skin culture mimicking the pathophysiological environment of cutaneous melanoma, we found that (1) L1 expression mostly correlates with melanoma progression and alphavbeta3 integrin expression, (2) overexpression of L1 in early radial growth phase melanoma cells promotes conversion from radial to vertical growth phase melanoma without upregulation of alphavbeta3 integrin expression, and (3) suppression of L1 function significantly reduces migration and invasion of melanoma cells, but does not completely block invasive melanoma growth. Altogether, L1 plays a critical role in melanoma invasion and progression and offers therapeutic potential in combination with conventional anticancer agents.

    International journal of cancer 2006;119;3;549-55

  • Alpha2-macroglobulin, lipoprotein receptor-related protein and lipoprotein receptor-associated protein and the genetic risk for developing Alzheimer's disease.

    Depboylu C, Lohmüller F, Du Y, Riemenschneider M, Kurz A, Gasser T, Müller U and Dodel RC

    Department of Neurology, Philipps University Marburg, Rudolph-Bultmann-Str. 8, 35039 Marburg, Germany. depboylu@med.uni-marburg.de

    Alpha2-macroglobulin (alpha2M) as well as its receptor, the low-density lipoprotein receptor-related (LRP) and the receptor-associated protein (RAP) are involved in the clearance of cerebral A beta. Current evidence suggests that polymorphisms in the genes of alpha2M, LRP and RAP may have functional effects on the proteins. Two independent association samples of 271 AD patients and 280 representative controls were investigated whether the risk for developing AD is altered in carriers of polymorphisms in the alpha2M-gene (Va1000Ile), in the LRP-gene (Ala216Val) and in the RAP-gene (Val311Met). Genotypes were determined by standard PCR and restriction fragment length polymorphism. The results were adjusted for age, gender and apolipoprotein E-epsilon4 (APOE) polymorphism. Inheritance of alpha2M conferred a small increased risk for sporadic AD with an estimated Mantel-Haenszel odds ratio of 1.47. There was no age- or gender-dependent increase in alpha2M Val1000Ile allele frequencies in AD patients compared to controls. There was no significant difference in the allele frequencies among control and AD subjects for the LRP and RAP polymorphisms. We found no evidence of an interaction between the alpha2M and RAP or LRP with regard to conferred risk. Our data suggest that the alpha2M Val1000Ile polymorphism is weakly associated with AD. Although LRP as well as RAP seem to play an essential role in the metabolism of alpha2M and APOE, there is no increase in the genetic risk for AD in patients carrying the investigated polymorphisms.

    Neuroscience letters 2006;400;3;187-90

  • A novel missense mutation in the L1CAM gene in a boy with L1 disease.

    Simonati A, Boaretto F, Vettori A, Dabrilli P, Criscuolo L, Rizzuto N and Mostacciuolo ML

    Department of Neurological and Visual Science, Section of Clinical Neurology-Child Neurology Unit, Policlinico G. B. Rossi, Verona, and Department of Biology, Laboratory of Human Genetics, University of Pauda, Italy. alessandro.simonati@univr.it

    A novel missense mutation of the L1CAM gene (Xq28) is described in an adult patient affected with severe mental retardation, spastic paraparesis, adducted thumbs, agenesis of corpus callosum and microcephaly (L1 disease). We detected a transition c2308G-->A in exon 18 that caused an amino acid change in codon 770. The patient's mother and two sisters were heterozygous for the same mutation. This newly described mutation predicts the substitution of an aspartate by asparagine (D770N) in the second fibronectin (Fn2) domain of the extracellular portion of the mature L1 protein. Even if amino acid substitution does not significantly change the physico-chemical properties of the Fn2 domain, it seems clear that the integrity of this domain is required to maintain the biological functions of the protein. The feature peculiar to this patient is the decelerated head growth post-natally, leading to microcephaly. Mutations of L1CAM associated with prolonged survival may hamper post-natal brain and head growth.

    Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology 2006;27;2;114-7

  • Expanding the phenotypic spectrum of L1CAM-associated disease.

    Basel-Vanagaite L, Straussberg R, Friez MJ, Inbar D, Korenreich L, Shohat M and Schwartz CE

    Department of Medical Genetics, Rabin Medical Center, Beilinson Campus, Petah Tikva, Israel. basel@post.tau.ac.il

    Mutations in the L1CAM gene cause neurological abnormalities of variable severity, including congenital hydrocephalus, agenesis of the corpus callosum, spastic paraplegia, bilaterally adducted thumbs, aphasia, and mental retardation. Inter- and intrafamilial variability is a well-known feature of the L1CAM spectrum, and several patients have a combination of L1CAM mutations and Hirschsprung's disease (HSCR). We report on two siblings with a missense mutation in exon 7 (p.P240L) of the L1CAM gene. In one of the siblings, congenital dislocation of the radial heads and HSCR were present. Neither patient had hydrocephalus, adducted thumbs, or absent speech, but both had a hypoplastic corpus callosum. We suggest that L1CAM mutation testing should be considered in male patients with a positive family history compatible with X-linked inheritance and either the combination of agenesis of the CC and HSCR or the combination of agenesis of the CC and limb abnormalities, including abnormalities other than adducted thumbs.

    Funded by: NICHD NIH HHS: HD26202

    Clinical genetics 2006;69;5;414-9

  • L1 (CD171) is highly expressed in gastrointestinal stromal tumors.

    Kaifi JT, Strelow A, Schurr PG, Reichelt U, Yekebas EF, Wachowiak R, Quaas A, Strate T, Schaefer H, Sauter G, Schachner M and Izbicki JR

    Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. jkaifi@uke.uni-hamburg.de

    The treatment strategy for mesenchymal tumors of the gastrointestinal tract is based upon typing of the tumor. Especially differential diagnosis of gastrointestinal stromal tumors (GISTs) to leiomyomas is crucial for determining radicality of surgery. L1 cell adhesion molecule (CD171) plays an essential role in tumor progression. The aim of this study was to determine expression of L1 in GISTs, smooth muscle tumors, desmoid-type fibromatosis and peripheral nerve sheath tumors (PNSTs). We retrospectively analyzed a total of 129 surgically resected primary tumors or metastases of 72 GISTs, 29 smooth muscle tumors, seven PNSTs and 21 desmoid-type fibromatosis by immunohistochemistry for c-kit, CD34, smooth muscle actin, desmin, vimentin, S-100 and L1 expression. L1 expression was detected in 53 (74%) of 72 GISTs but in none of 29 smooth muscle tumors or 21 desmoid-type fibromatosis (P<0.01 by Fisher's test). In all, four (57%) of seven peripheral nerve sheath tumors were L1-positive. Survival analysis of 55 surgically completely resected GISTs presenting without metastasis at initial diagnosis revealed no tumor-specific death among L1-negative patients (P=0.13 by log-rank test; median follow-up time 41 months) and one recurrence was observed (P=0.12). Interestingly high levels of L1 were seen in tumor vascular endothelial cells of smooth muscle tumors and PNSTs, but not in GISTs. Our data show that L1 is highly expressed in GISTs but not in smooth muscle tumors and desmoid-type fibromatosis being important differential diagnoses. The trend towards a reduced survival of L1-positive patients in this study has to be further evaluated in future trials with higher patient numbers.

    Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 2006;19;3;399-406

  • A role for exosomes in the constitutive and stimulus-induced ectodomain cleavage of L1 and CD44.

    Stoeck A, Keller S, Riedle S, Sanderson MP, Runz S, Le Naour F, Gutwein P, Ludwig A, Rubinstein E and Altevogt P

    Tumor Immunology Programme, D010, German Cancer Research Center, Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany.

    Ectodomain shedding is a proteolytic mechanism by which transmembrane molecules are converted into a soluble form. Cleavage is mediated by metalloproteases and proceeds in a constitutive or inducible fashion. Although believed to be a cell-surface event, there is increasing evidence that cleavage can take place in intracellular compartments. However, it is unknown how cleaved soluble molecules get access to the extracellular space. By analysing L1 (CD171) and CD44 in ovarian carcinoma cells, we show in the present paper that the cleavage induced by ionomycin, APMA (4-aminophenylmercuric acetate) or MCD (methyl-beta-cyclodextrin) is initiated in an endosomal compartment that is subsequently released in the form of exosomes. Calcium influx augmented the release of exosomes containing functionally active forms of ADAM10 (a disintegrin and metalloprotease 10) and ADAM17 [TACE (tumour necrosis factor a-converting enzyme)] as well as CD44 and L1 cytoplasmic cleavage fragments. Cleavage could also proceed in released exosomes, but only depletion of ADAM10 by small interfering RNA blocked cleavage under constitutive and induced conditions. In contrast, cleavage of L1 in response to PMA occurred at the cell surface and was mediated by ADAM17. We conclude that different ADAMs are involved in distinct cellular compartments and that ADAM10 is responsible for shedding in vesicles. Our findings open up the possibility that exosomes serve as a platform for ectodomain shedding and as a vehicle for the cellular export of soluble molecules.

    The Biochemical journal 2006;393;Pt 3;609-18

  • A conserved role for Drosophila Neuroglian and human L1-CAM in central-synapse formation.

    Godenschwege TA, Kristiansen LV, Uthaman SB, Hortsch M and Murphey RK

    Department of Biology, Morrill Science Center, University of Massachusetts, Amherst, Amherst, Massachusetts 01003, USA. tanjag@bio.umass.edu

    Background: Drosophila Neuroglian (Nrg) and its vertebrate homolog L1-CAM are cell-adhesion molecules (CAM) that have been well studied in early developmental processes. Mutations in the human gene result in a broad spectrum of phenotypes (the CRASH-syndrome) that include devastating neurological disorders such as spasticity and mental retardation. Although the role of L1-CAMs in neurite extension and axon pathfinding has been extensively studied, much less is known about their role in synapse formation.

    Results: We found that a single extracellular missense mutation in nrg(849) mutants disrupted the physiological function of a central synapse in Drosophila. The identified giant neuron in nrg(849) mutants made a synaptic terminal on the appropriate target, but ultrastructural analysis revealed in the synaptic terminal a dramatic microtubule reduction, which was likely to be the cause for disrupted active zones. Our results reveal that tyrosine phosphorylation of the intracellular ankyrin binding motif was reduced in mutants, and cell-autonomous rescue experiments demonstrated the indispensability of this tyrosine in giant-synapse formation. We also show that this function in giant-synapse formation was conserved in human L1-CAM but neither in human L1-CAM with a pathological missense mutation nor in two isoforms of the paralogs NrCAM and Neurofascin.

    Conclusions: We conclude that Nrg has a function in synapse formation by organizing microtubules in the synaptic terminal. This novel synaptic function is conserved in human L1-CAM but is not common to all L1-type proteins. Finally, our findings suggest that some aspects of L1-CAM-related neurological disorders in humans may result from a disruption in synapse formation rather than in axon pathfinding.

    Funded by: NINDS NIH HHS: R01-NS044609

    Current biology : CB 2006;16;1;12-23

  • The extent of linkage disequilibrium caused by selection on G6PD in humans.

    Saunders MA, Slatkin M, Garner C, Hammer MF and Nachman MW

    Department of Ecology and Evolutionary Biology, University of Arizona, Tucson, Arizona 85721, USA. saunders@uchicago.edu

    The gene coding for glucose-6-phosphate dehydrogenase (G6PD) is subject to positive selection by malaria in some human populations. The G6PD A- allele, which is common in sub-Saharan Africa, is associated with deficient enzyme activity and protection from severe malaria. To delimit the impact of selection on patterns of linkage disequilibrium (LD) and nucleotide diversity, we resequenced 5.1 kb at G6PD and approximately 2-3 kb at each of eight loci in a 2.5-Mb region roughly centered on G6PD in a diverse sub-Saharan African panel of 51 unrelated men (including 20 G6PD A-, 11 G6PD A+, and 20 G6PD B chromosomes). The signature of selection is evident in the absence of genetic variation at G6PD and at three neighboring loci within 0.9 Mb from G6PD among all individuals bearing G6PD A- alleles. A genomic region of approximately 1.6 Mb around G6PD was characterized by long-range LD associated with the A- alleles. These patterns of nucleotide variability and LD suggest that G6PD A- is younger than previous age estimates and has increased in frequency in sub-Saharan Africa due to strong selection (0.1 < s < 0.2). These results also show that selection can lead to nonrandom associations among SNPs over great physical and genetic distances, even in African populations.

    Genetics 2005;171;3;1219-29

  • Human plasma N-glycoproteome analysis by immunoaffinity subtraction, hydrazide chemistry, and mass spectrometry.

    Liu T, Qian WJ, Gritsenko MA, Camp DG, Monroe ME, Moore RJ and Smith RD

    Biological Sciences Division and Environmental Molecular Sciences Laboratory, Pacific Northwest National Laboratory, Richland, Washington 99354, USA.

    The enormous complexity, wide dynamic range of relative protein abundances of interest (over 10 orders of magnitude), and tremendous heterogeneity (due to post-translational modifications, such as glycosylation) of the human blood plasma proteome severely challenge the capabilities of existing analytical methodologies. Here, we describe an approach for broad analysis of human plasma N-glycoproteins using a combination of immunoaffinity subtraction and glycoprotein capture to reduce both the protein concentration range and the overall sample complexity. Six high-abundance plasma proteins were simultaneously removed using a pre-packed, immobilized antibody column. N-linked glycoproteins were then captured from the depleted plasma using hydrazide resin and enzymatically digested, and the bound N-linked glycopeptides were released using peptide-N-glycosidase F (PNGase F). Following strong cation exchange (SCX) fractionation, the deglycosylated peptides were analyzed by reversed-phase capillary liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS). Using stringent criteria, a total of 2053 different N-glycopeptides were confidently identified, covering 303 nonredundant N-glycoproteins. This enrichment strategy significantly improved detection and enabled identification of a number of low-abundance proteins, exemplified by interleukin-1 receptor antagonist protein (approximately 200 pg/mL), cathepsin L (approximately 1 ng/mL), and transforming growth factor beta 1 (approximately 2 ng/mL). A total of 639 N-glycosylation sites were identified, and the overall high accuracy of these glycosylation site assignments as assessed by accurate mass measurement using high-resolution liquid chromatography coupled to Fourier transform ion cyclotron resonance mass spectrometry (LC-FTICR) is initially demonstrated.

    Funded by: NCRR NIH HHS: P41 RR018522, RR18522; NIGMS NIH HHS: U54 GM-62119-02, U54 GM062119

    Journal of proteome research 2005;4;6;2070-80

  • A human protein-protein interaction network: a resource for annotating the proteome.

    Stelzl U, Worm U, Lalowski M, Haenig C, Brembeck FH, Goehler H, Stroedicke M, Zenkner M, Schoenherr A, Koeppen S, Timm J, Mintzlaff S, Abraham C, Bock N, Kietzmann S, Goedde A, Toksöz E, Droege A, Krobitsch S, Korn B, Birchmeier W, Lehrach H and Wanker EE

    Max Delbrueck Center for Molecular Medicine, 13092 Berlin-Buch, Germany.

    Protein-protein interaction maps provide a valuable framework for a better understanding of the functional organization of the proteome. To detect interacting pairs of human proteins systematically, a protein matrix of 4456 baits and 5632 preys was screened by automated yeast two-hybrid (Y2H) interaction mating. We identified 3186 mostly novel interactions among 1705 proteins, resulting in a large, highly connected network. Independent pull-down and co-immunoprecipitation assays validated the overall quality of the Y2H interactions. Using topological and GO criteria, a scoring system was developed to define 911 high-confidence interactions among 401 proteins. Furthermore, the network was searched for interactions linking uncharacterized gene products and human disease proteins to regulatory cellular pathways. Two novel Axin-1 interactions were validated experimentally, characterizing ANP32A and CRMP1 as modulators of Wnt signaling. Systematic human protein interaction screens can lead to a more comprehensive understanding of protein function and cellular processes.

    Cell 2005;122;6;957-68

  • RanBPM is an L1-interacting protein that regulates L1-mediated mitogen-activated protein kinase activation.

    Cheng L, Lemmon S and Lemmon V

    Department of Neurosciences, Case Western Reserve University, Cleveland, Ohio, USA.

    A yeast two-hybrid screen using the last 28 amino acids of the cytoplasmic domain of the neural cell adhesion molecule L1 identified RanBPM as an L1-interacting protein. RanBPM associates with L1 in vivo and the N-terminal region of RanBPM (N-RanBPM), containing the SPRY domain, is sufficient for the interaction with L1 in a glutathione S-transferase pull-down assay. L1 antibody patching dramatically changes the subcellular localization of N-RanBPM in transfected COS cells. Overexpression of N-RanBPM in COS cells reduces L1-triggered extracellular signal-regulated kinase 1/2 activation by 50% and overexpression of N-RanBPM in primary neurons inhibits L1-mediated neurite outgrowth and branching. These data suggest that RanBPM is an adaptor protein that links L1 to the extracellular signal-regulated kinase/MAPK pathway.

    Funded by: NEI NIH HHS: R01 EY005285, R01 EY005285-23; NICHD NIH HHS: R01 HD039884, R01 HD039884-06

    Journal of neurochemistry 2005;94;4;1102-10

  • Transcriptional maps of 10 human chromosomes at 5-nucleotide resolution.

    Cheng J, Kapranov P, Drenkow J, Dike S, Brubaker S, Patel S, Long J, Stern D, Tammana H, Helt G, Sementchenko V, Piccolboni A, Bekiranov S, Bailey DK, Ganesh M, Ghosh S, Bell I, Gerhard DS and Gingeras TR

    Affymetrix Inc., Santa Clara, CA 95051, USA.

    Sites of transcription of polyadenylated and nonpolyadenylated RNAs for 10 human chromosomes were mapped at 5-base pair resolution in eight cell lines. Unannotated, nonpolyadenylated transcripts comprise the major proportion of the transcriptional output of the human genome. Of all transcribed sequences, 19.4, 43.7, and 36.9% were observed to be polyadenylated, nonpolyadenylated, and bimorphic, respectively. Half of all transcribed sequences are found only in the nucleus and for the most part are unannotated. Overall, the transcribed portions of the human genome are predominantly composed of interlaced networks of both poly A+ and poly A- annotated transcripts and unannotated transcripts of unknown function. This organization has important implications for interpreting genotype-phenotype associations, regulation of gene expression, and the definition of a gene.

    Science (New York, N.Y.) 2005;308;5725;1149-54

  • Alterations in cell adhesion molecule L1 and functionally related genes in major depression: a postmortem study.

    Laifenfeld D, Karry R, Klein E and Ben-Shachar D

    Laboratory of Psychobiology, The Department of Psychiatry, Rambam Medical Center, and B. Rappaport Faculty of Medicine, Technion IIT, Haifa, Israel.

    Background: Current research in depression aims to delineate genes involved in neuronal plasticity that are altered in the disease or its treatment. We have shown antidepressant induced increases in three interrelated genes, cell adhesion molecule L1 (CAM-L1), laminin, and cAMP response element binding protein (CREB), and a reciprocal decrease in these genes consequent to stress. Presently we hypothesized that CAM-L1, CREB, and laminin may be altered in post mortem brains of depressed subjects.

    Methods: Studies were performed in the prefrontal and in the ventral parieto-occipital cortices, of 59 brains from depressed, bipolar, and schizophrenic subjects, and normal controls, obtained from the Stanley Foundation Brain Collection. mRNA and protein levels were determined by RT-PCR and Western blot analysis, respectively.

    Results: Levels of CAM-L1 and of phosphorylated CREB (pCREB) were increased in the prefrontal cortex of the depressed group, while CAM-L1, laminin and pCREB were decreased in the parieto-occipital cortex. Depressed subjects receiving antidepressants differed from subjects not receiving antidepressants in the expression of CAM-L1 and laminin in the parieto-occipital cortex, and in the expression of pCREB in the prefrontal cortex.

    Conclusions: The present findings of specific alterations in depression and antidepressant treatment particularly in CAM-L1 suggest that this gene may play an important role in the pathophysiology and treatment of depression.

    Biological psychiatry 2005;57;7;716-25

  • The DNA sequence of the human X chromosome.

    Ross MT, Grafham DV, Coffey AJ, Scherer S, McLay K, Muzny D, Platzer M, Howell GR, Burrows C, Bird CP, Frankish A, Lovell FL, Howe KL, Ashurst JL, Fulton RS, Sudbrak R, Wen G, Jones MC, Hurles ME, Andrews TD, Scott CE, Searle S, Ramser J, Whittaker A, Deadman R, Carter NP, Hunt SE, Chen R, Cree A, Gunaratne P, Havlak P, Hodgson A, Metzker ML, Richards S, Scott G, Steffen D, Sodergren E, Wheeler DA, Worley KC, Ainscough R, Ambrose KD, Ansari-Lari MA, Aradhya S, Ashwell RI, Babbage AK, Bagguley CL, Ballabio A, Banerjee R, Barker GE, Barlow KF, Barrett IP, Bates KN, Beare DM, Beasley H, Beasley O, Beck A, Bethel G, Blechschmidt K, Brady N, Bray-Allen S, Bridgeman AM, Brown AJ, Brown MJ, Bonnin D, Bruford EA, Buhay C, Burch P, Burford D, Burgess J, Burrill W, Burton J, Bye JM, Carder C, Carrel L, Chako J, Chapman JC, Chavez D, Chen E, Chen G, Chen Y, Chen Z, Chinault C, Ciccodicola A, Clark SY, Clarke G, Clee CM, Clegg S, Clerc-Blankenburg K, Clifford K, Cobley V, Cole CG, Conquer JS, Corby N, Connor RE, David R, Davies J, Davis C, Davis J, Delgado O, Deshazo D, Dhami P, Ding Y, Dinh H, Dodsworth S, Draper H, Dugan-Rocha S, Dunham A, Dunn M, Durbin KJ, Dutta I, Eades T, Ellwood M, Emery-Cohen A, Errington H, Evans KL, Faulkner L, Francis F, Frankland J, Fraser AE, Galgoczy P, Gilbert J, Gill R, Glöckner G, Gregory SG, Gribble S, Griffiths C, Grocock R, Gu Y, Gwilliam R, Hamilton C, Hart EA, Hawes A, Heath PD, Heitmann K, Hennig S, Hernandez J, Hinzmann B, Ho S, Hoffs M, Howden PJ, Huckle EJ, Hume J, Hunt PJ, Hunt AR, Isherwood J, Jacob L, Johnson D, Jones S, de Jong PJ, Joseph SS, Keenan S, Kelly S, Kershaw JK, Khan Z, Kioschis P, Klages S, Knights AJ, Kosiura A, Kovar-Smith C, Laird GK, Langford C, Lawlor S, Leversha M, Lewis L, Liu W, Lloyd C, Lloyd DM, Loulseged H, Loveland JE, Lovell JD, Lozado R, Lu J, Lyne R, Ma J, Maheshwari M, Matthews LH, McDowall J, McLaren S, McMurray A, Meidl P, Meitinger T, Milne S, Miner G, Mistry SL, Morgan M, Morris S, Müller I, Mullikin JC, Nguyen N, Nordsiek G, Nyakatura G, O'Dell CN, Okwuonu G, Palmer S, Pandian R, Parker D, Parrish J, Pasternak S, Patel D, Pearce AV, Pearson DM, Pelan SE, Perez L, Porter KM, Ramsey Y, Reichwald K, Rhodes S, Ridler KA, Schlessinger D, Schueler MG, Sehra HK, Shaw-Smith C, Shen H, Sheridan EM, Shownkeen R, Skuce CD, Smith ML, Sotheran EC, Steingruber HE, Steward CA, Storey R, Swann RM, Swarbreck D, Tabor PE, Taudien S, Taylor T, Teague B, Thomas K, Thorpe A, Timms K, Tracey A, Trevanion S, Tromans AC, d'Urso M, Verduzco D, Villasana D, Waldron L, Wall M, Wang Q, Warren J, Warry GL, Wei X, West A, Whitehead SL, Whiteley MN, Wilkinson JE, Willey DL, Williams G, Williams L, Williamson A, Williamson H, Wilming L, Woodmansey RL, Wray PW, Yen J, Zhang J, Zhou J, Zoghbi H, Zorilla S, Buck D, Reinhardt R, Poustka A, Rosenthal A, Lehrach H, Meindl A, Minx PJ, Hillier LW, Willard HF, Wilson RK, Waterston RH, Rice CM, Vaudin M, Coulson A, Nelson DL, Weinstock G, Sulston JE, Durbin R, Hubbard T, Gibbs RA, Beck S, Rogers J and Bentley DR

    The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK. mtr@sanger.ac.uk

    The human X chromosome has a unique biology that was shaped by its evolution as the sex chromosome shared by males and females. We have determined 99.3% of the euchromatic sequence of the X chromosome. Our analysis illustrates the autosomal origin of the mammalian sex chromosomes, the stepwise process that led to the progressive loss of recombination between X and Y, and the extent of subsequent degradation of the Y chromosome. LINE1 repeat elements cover one-third of the X chromosome, with a distribution that is consistent with their proposed role as way stations in the process of X-chromosome inactivation. We found 1,098 genes in the sequence, of which 99 encode proteins expressed in testis and in various tumour types. A disproportionately high number of mendelian diseases are documented for the X chromosome. Of this number, 168 have been explained by mutations in 113 X-linked genes, which in many cases were characterized with the aid of the DNA sequence.

    Funded by: NHGRI NIH HHS: U54 HG003273

    Nature 2005;434;7031;325-37

  • L1, a novel target of beta-catenin signaling, transforms cells and is expressed at the invasive front of colon cancers.

    Gavert N, Conacci-Sorrell M, Gast D, Schneider A, Altevogt P, Brabletz T and Ben-Ze'ev A

    Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, 76100, Israel.

    Aberrant beta-catenin-TCF target gene activation plays a key role in colorectal cancer, both in the initiation stage and during invasion and metastasis. We identified the neuronal cell adhesion molecule L1, as a target gene of beta-catenin-TCF signaling in colorectal cancer cells. L1 expression was high in sparse cultures and coregulated with ADAM10, a metalloprotease involved in cleaving and shedding L1's extracellular domain. L1 expression conferred increased cell motility, growth in low serum, transformation and tumorigenesis, whereas its suppression in colon cancer cells decreased motility. L1 was exclusively localized in the invasive front of human colorectal tumors together with ADAM10. The transmembrane localization and shedding of L1 by metalloproteases could be useful for detection and as target for colon cancer therapy.

    The Journal of cell biology 2005;168;4;633-42

  • L1-mediated branching is regulated by two ezrin-radixin-moesin (ERM)-binding sites, the RSLE region and a novel juxtamembrane ERM-binding region.

    Cheng L, Itoh K and Lemmon V

    Department of Neurosciences, Case Western Reserve University, Cleveland, Ohio 44106, USA.

    We investigated how the neural cell adhesion molecule L1 mediates neurite outgrowth through L1-L1 homophilic interactions. Wild-type L1 and L1 with mutations in the cytoplasmic domain (CD) were introduced into L1 knock-out neurons, and transfected neurons were grown on an L1 substrate. Neurite length and branching were compared between wild-type L1 and L1CD mutations. Surprisingly, the L1CD is not required for L1-mediated neurite outgrowth but plays a critical role in neurite branching, through both the juxtamembrane region and the RSLE region. We demonstrate that both regions serve as ezrin-moesin-radixin-binding sites. A truncation mutant that deletes 110 of 114 amino acids of the L1CD still supports neurite outgrowth on an L1 substrate, suggesting that a coreceptor binds to L1 in cis and mediates neurite outgrowth and that L1-ankyrin interactions are not essential for neurite initiation or outgrowth. These data are consistent with a model in which L1 can influence L1-mediated neurite outgrowth and branching through both the L1CD and a coreceptor.

    Funded by: NEI NIH HHS: EY-05285, EY-11373, P30 EY011373, R01 EY005285, R01 EY005285-23; NICHD NIH HHS: HD39884, R01 HD039884, R01 HD039884-06

    The Journal of neuroscience : the official journal of the Society for Neuroscience 2005;25;2;395-403

  • The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).

    Gerhard DS, Wagner L, Feingold EA, Shenmen CM, Grouse LH, Schuler G, Klein SL, Old S, Rasooly R, Good P, Guyer M, Peck AM, Derge JG, Lipman D, Collins FS, Jang W, Sherry S, Feolo M, Misquitta L, Lee E, Rotmistrovsky K, Greenhut SF, Schaefer CF, Buetow K, Bonner TI, Haussler D, Kent J, Kiekhaus M, Furey T, Brent M, Prange C, Schreiber K, Shapiro N, Bhat NK, Hopkins RF, Hsie F, Driscoll T, Soares MB, Casavant TL, Scheetz TE, Brown-stein MJ, Usdin TB, Toshiyuki S, Carninci P, Piao Y, Dudekula DB, Ko MS, Kawakami K, Suzuki Y, Sugano S, Gruber CE, Smith MR, Simmons B, Moore T, Waterman R, Johnson SL, Ruan Y, Wei CL, Mathavan S, Gunaratne PH, Wu J, Garcia AM, Hulyk SW, Fuh E, Yuan Y, Sneed A, Kowis C, Hodgson A, Muzny DM, McPherson J, Gibbs RA, Fahey J, Helton E, Ketteman M, Madan A, Rodrigues S, Sanchez A, Whiting M, Madari A, Young AC, Wetherby KD, Granite SJ, Kwong PN, Brinkley CP, Pearson RL, Bouffard GG, Blakesly RW, Green ED, Dickson MC, Rodriguez AC, Grimwood J, Schmutz J, Myers RM, Butterfield YS, Griffith M, Griffith OL, Krzywinski MI, Liao N, Morin R, Morrin R, Palmquist D, Petrescu AS, Skalska U, Smailus DE, Stott JM, Schnerch A, Schein JE, Jones SJ, Holt RA, Baross A, Marra MA, Clifton S, Makowski KA, Bosak S, Malek J and MGC Project Team

    The National Institutes of Health's Mammalian Gene Collection (MGC) project was designed to generate and sequence a publicly accessible cDNA resource containing a complete open reading frame (ORF) for every human and mouse gene. The project initially used a random strategy to select clones from a large number of cDNA libraries from diverse tissues. Candidate clones were chosen based on 5'-EST sequences, and then fully sequenced to high accuracy and analyzed by algorithms developed for this project. Currently, more than 11,000 human and 10,000 mouse genes are represented in MGC by at least one clone with a full ORF. The random selection approach is now reaching a saturation point, and a transition to protocols targeted at the missing transcripts is now required to complete the mouse and human collections. Comparison of the sequence of the MGC clones to reference genome sequences reveals that most cDNA clones are of very high sequence quality, although it is likely that some cDNAs may carry missense variants as a consequence of experimental artifact, such as PCR, cloning, or reverse transcriptase errors. Recently, a rat cDNA component was added to the project, and ongoing frog (Xenopus) and zebrafish (Danio) cDNA projects were expanded to take advantage of the high-throughput MGC pipeline.

    Funded by: PHS HHS: N01-C0-12400

    Genome research 2004;14;10B;2121-7

  • Congenital idiopathic intestinal pseudo-obstruction and hydrocephalus with stenosis of the aqueduct of sylvius.

    Bott L, Boute O, Mention K, Vinchon M, Boman F and Gottrand F

    Pediatric Gastro-Enterology, Hepatology and Nutrition Unit, Jeanne de Flandre Hospital, Faculty of Medicine Lille, France.

    We present the first report of an association between hydrocephalus with stenosis of the aqueduct of Sylvius (HSAS) and a specific form of congenital idiopathic intestinal pseudo-obstruction (CIIP) in an infant. Diagnosis of HSAS was suspected during the neonatal period because of a severely dilated ventricular system associated with bilateral adducted thumbs, and was confirmed by demonstration of a mutation in the gene encoding L1 cell adhesion molecule (L1CAM). L1CAM mutations cause a variable clinical spectrum. This gene is located at Xq28 and encodes a transmembrane glycoprotein involved in neurite outgrowth and neuronal migration. Hirschprung disease has been reported to involve an L1CAM mutation that manifests as a quantitative defect in the migration of neural crest cells in distal segments of the gut. We report an association that suggests that alterations of L1CAM may cause another type of intestinal pseudo-obstruction distension with a qualitative defect in differentiated Cajal's cells in the anterior part of the gut. This observation suggests that L1CAM has a role in the developmental regulation of multiple systems. Further clinical descriptions of gastroenterological and neuropathological data are required to extend our understanding of the mechanisms underlying L1CAM functions.

    American journal of medical genetics. Part A 2004;130A;1;84-7

  • Extracellular signal-regulated kinase (ERK)-dependent gene expression contributes to L1 cell adhesion molecule-dependent motility and invasion.

    Silletti S, Yebra M, Perez B, Cirulli V, McMahon M and Montgomery AM

    Department of Pediatrics, The Whittier Institute, and Moores Comprehensive Cancer Center, University of California at San Diego, La Jolla, California 92037, USA.

    The cell adhesion molecule L1 has been implicated in a variety of motile processes, including neurite extension, cerebellar cell migration, extravasation, and metastasis. Homophilic or heterophilic L1 binding and concomitant signaling have been shown to promote cell motility in the short term. In this report, L1 is also shown to induce and maintain a motile and invasive phenotype by promoting gene transcription. In the presence of serum or platelet-derived growth factor, L1 promotes heightened and sustained activation of the extracellular signal-regulated kinase pathway. Activation of this pathway then induces the expression of motility- and invasion-associated gene products, including the beta(3)-integrin subunit, small GTPases, and the cysteine proteases cathepsin-L and -B. Induction of integrin alpha(v)beta(3) and rac-1 is shown to contribute directly to L1-dependent haptotaxis, whereas induction of cathepsins-L and -B promotes matrix invasion. This study provides a novel translational mechanism to account for the association between L1 expression and motile processes involved in metastasis and development.

    Funded by: NCI NIH HHS: R01 CA69112-01; NHLBI NIH HHS: R01 HL62477-01; NIDDK NIH HHS: R01 DK55183, R01 DK55183S1

    The Journal of biological chemistry 2004;279;28;28880-8

  • Time-controlled transcardiac perfusion cross-linking for the study of protein interactions in complex tissues.

    Schmitt-Ulms G, Hansen K, Liu J, Cowdrey C, Yang J, DeArmond SJ, Cohen FE, Prusiner SB and Baldwin MA

    Institute for Neurodegenerative Disease, San Francisco, California 94143, USA. g.schmittulms@utoronto.ca

    Because of their sensitivity to solubilizing detergents, membrane protein assemblies are difficult to study. We describe a protocol that covalently conserves protein interactions through time-controlled transcardiac perfusion cross-linking (tcTPC) before disruption of tissue integrity. To validate tcTPC for identifying protein-protein interactions, we established that tcTPC allowed stringent immunoaffinity purification of the gamma-secretase complex in high salt concentrations and detergents and was compatible with mass spectrometric identification of cross-linked aph-1, presenilin-1 and nicastrin. We then applied tcTPC to identify more than 20 proteins residing in the vicinity of the cellular prion protein (PrPC), suggesting that PrP is embedded in specialized membrane regions with a subset of molecules that, like PrP, use a glycosylphosphatidylinositol anchor for membrane attachment. Many of these proteins have been implicated in cell adhesion/neuritic outgrowth, and harbor immunoglobulin C2 and fibronectin type III-like motifs.

    Funded by: NCRR NIH HHS: NCRR RR01614; NIA NIH HHS: AG010770, AG02132

    Nature biotechnology 2004;22;6;724-31

  • LGI1 mutations in autosomal dominant partial epilepsy with auditory features.

    Ottman R, Winawer MR, Kalachikov S, Barker-Cummings C, Gilliam TC, Pedley TA and Hauser WA

    Gertrude H. Sergievsky Center, Columbia University, New York, NY 10032, USA. ro6@columbia.edu

    Objective: S: Mutations in LGI1 cause autosomal dominant partial epilepsy with auditory features (ADPEAF), a form of familial temporal lobe epilepsy with auditory ictal manifestations. The authors aimed to determine what proportion of ADPEAF families carries a mutation, to estimate the penetrance of identified mutations, and to identify clinical features that distinguish families with and without mutations.

    Methods: The authors sequenced LGI1 in 10 newly described ADPEAF families and analyzed clinical features in these families and others with mutations reported previously.

    Results: Three of the families had missense mutations in LGI1 (C42R, I298T, and A110D). Penetrance was 54% in eight families with LGI1 mutations the authors have identified so far (five reported previously and three reported here). Excluding the original linkage family, the authors have found mutations in 50% (7/14) of tested families. Families with and without mutations had similar clinical features, but those with mutations contained significantly more subjects with auditory symptoms and significantly fewer with autonomic symptoms. In families with mutations, the most common auditory symptom type was simple, unformed sounds (e.g., buzzing and ringing). In two of the newly identified families with mutations, some subjects with mutations had idiopathic generalized epilepsies.

    Conclusions: LGI1 mutations are a common cause of autosomal dominant partial epilepsy with auditory features. Current data do not reveal a clinical feature that clearly predicts which families with autosomal dominant partial epilepsy with auditory features have a mutation. Some families with LGI1 mutations contain individuals with idiopathic generalized epilepsies. This could result from either an effect of LGI1 on risk for generalized epilepsy or an effect of co-occurring idiopathic generalized epilepsy-specific genes in these families.

    Funded by: NINDS NIH HHS: R01 NS020656, R01 NS036319, R01 NS036319-08, R01 NS043472, R01 NS043472-05, R01 NS36319

    Neurology 2004;62;7;1120-6

  • LGI1 mutations in temporal lobe epilepsies.

    Berkovic SF, Izzillo P, McMahon JM, Harkin LA, McIntosh AM, Phillips HA, Briellmann RS, Wallace RH, Mazarib A, Neufeld MY, Korczyn AD, Scheffer IE and Mulley JC

    Epilepsy Research Institute and Department of Medicine, University of Melbourne, Victoria, Australia. s.berkovic@unimelb.edu.au

    A number of familial temporal lobe epilepsies (TLE) have been recently recognized. Mutations in LGI1 (leucine-rich, glioma-inactivated 1 gene) have been found in a few families with the syndrome of autosomal dominant partial epilepsy with auditory features (ADPEAF). The authors aimed to determine the spectrum of TLE phenotypes with LGI1 mutations, to study the frequency of mutations in ADPEAF, and to examine the role of LGI1 paralogs in ADPEAF without LGI1 mutations.

    Methods: The authors performed a clinical and molecular analysis on 75 pedigrees comprising 54 with a variety of familial epilepsies associated with TLE and 21 sporadic TLE cases. All were studied for mutations in LGI1. ADPEAF families negative for LGI1 mutations were screened for mutations in LGI2, LGI3, and LGI4.

    Results: Four families had ADPEAF, 22 had mesial TLE, 11 had TLE with febrile seizures, two had TLE with developmental abnormalities, and 15 had various other TLE syndromes. LGI1 mutations were found in two of four ADPEAF families, but in none of the other 50 families nor in the 21 individuals with sporadic TLE. The mutations were novel missense mutations in exons 1 (c.124T-->G; C42G) and 8 (c.1418C-->T; S473L). No mutations in LGI2, LGI3, or LGI4 were found in the other two ADPEAF families.

    Conclusion: In TLE, mutations in LGI1 are specific for ADPEAF but do not occur in all families. ADPEAF is genetically heterogeneous, but mutations in LGI2, LGI3, or LGI4 did not account for families without LGI1 mutations.

    Neurology 2004;62;7;1115-9

  • Activation of EGF receptor kinase by L1-mediated homophilic cell interactions.

    Islam R, Kristiansen LV, Romani S, Garcia-Alonso L and Hortsch M

    Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, Michigan 48109, USA.

    Neural cell adhesion molecules (CAMs) are important players during neurogenesis and neurite outgrowth as well as axonal fasciculation and pathfinding. Some of these developmental processes entail the activation of cellular signaling cascades. Pharmacological and genetic evidence indicates that the neurite outgrowth-promoting activity of L1-type CAMs is at least in part mediated by the stimulation of neuronal receptor tyrosine kinases (RTKs), especially FGF and EGF receptors. It has long been suspected that neural CAMs might physically interact with RTKs, but their activation by specific cell adhesion events has not been directly demonstrated. Here we report that gain-of-function conditions of the Drosophila L1-type CAM Neuroglian result in profound sensory axon pathfinding defects in the developing Drosophila wing. This phenotype can be suppressed by decreasing the normal gene dosage of the Drosophila EGF receptor gene. Furthermore, in Drosophila S2 cells, cell adhesion mediated by human L1-CAM results in the specific activation of human EGF tyrosine kinase at cell contact sites and EGF receptors engage in a physical interaction with L1-CAM molecules. Thus L1-type CAMs are able to promote the adhesion-dependent activation of EGF receptor signaling in vitro and in vivo.

    Funded by: NICHD NIH HHS: R01 HD029388, R01HD29388

    Molecular biology of the cell 2004;15;4;2003-12

  • Heterophilic interactions between cell adhesion molecule L1 and alphavbeta3-integrin induce HUVEC process extension in vitro and angiogenesis in vivo.

    Hall H, Djonov V, Ehrbar M, Hoechli M and Hubbell JA

    Institute for Biomedical Engineering and Department of Materials, ETH and University of Zurich, Zurich, Switzerland. heike.hall@mat.ethz.ch

    Cell adhesion molecule L1 was implicated in angiogenic processes, tumor formation and metastasis. Here, we provide evidence that the sixth Ig-like domain of L1 (L1Ig6) interacts with alpha(v)beta3 to induce process extension of human umbilical vein endothelial cells (HUVECs) in vitro and angiogenesis in vivo. HUVECs formed network-like structures on full-length L1 or L1Ig6 substrates comparable to structures found on matrigel. In the presence of mab alpha(v)beta3 or cyclic RGD, apoptosis was induced. In fibrin matrices where L1Ig6 was covalently incorporated, HUVECs formed multicellular and hollow processes through interactions between cell-surface alpha(v)beta3 and RGD-sites of matrix-immobilized L1Ig6. No such processes were induced by L1Ig6 having non-functional RDG-sites, or in the presence of mab alpha(v)beta3 or cyclic RGD. In those matrices, increased apoptosis was found. Co-immunoprecipitation of L1 or L1Ig6 with alpha(v)beta3 suggests close interactions. Furthermore, L1Ig6 stimulated HUVECs showed increased tyrosine phosphorylation of alpha(v)beta3 and phosphorylation of MAP kinases (ERK1 and ERK2) but not AKT indicating specific activation of alpha(v) and alpha(v)beta3 followed by activation of downstream kinases. Application of L1Ig6-modified fibrin matrices on CAMs induced 50-60% increased alpha(v) and alpha(v)beta3 protein expression and in vivo angiogenesis indicated by approximately 50% increased mean vascular length density. The results demonstrate angiogenic potential of L1Ig6 involving ligation and activation of alpha(v)beta3.

    Angiogenesis 2004;7;3;213-23

  • Hydrocephalus and Hirschsprung's disease with a mutation of L1CAM.

    Okamoto N, Del Maestro R, Valero R, Monros E, Poo P, Kanemura Y and Yamasaki M

    Department of Planning and Research, Osaka Medical Center and Research Institute for Maternal and Child Health, 840 Murodo-cho, Izumi, Osaka 594-1101, Japan. okamoto@osaka.email.ne.jp

    Abnormalities of the L1CAM gene, a member of the immunoglobulin gene superfamily of neural-cell adhesion molecules, are associated with X-linked hydrocephalus and some allelic disorders. Hirschsprung's disease (HSCR) is characterized by the absence of ganglion cells and the presence of hypertrophic nerve trunks in the distal bowel. There have been three reports of patients with X-linked hydrocephalus and HSCR with a mutation in the L1CAM gene. We report three more patients with similar conditions. We suspect that decreased L1CAM may be a modifying factor in the development of HSCR.

    Journal of human genetics 2004;49;6;334-7

  • L1-dependent neuritogenesis involves ankyrinB that mediates L1-CAM coupling with retrograde actin flow.

    Nishimura K, Yoshihara F, Tojima T, Ooashi N, Yoon W, Mikoshiba K, Bennett V and Kamiguchi H

    Laboratory for Neuronal Growth Mechanisms, Brain Science Institute, RIKEN, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan.

    The cell adhesion molecule L1 (L1-CAM) plays critical roles in neurite growth. Its cytoplasmic domain (L1CD) binds to ankyrins that associate with the spectrin-actin network. This paper demonstrates that L1-CAM interactions with ankyrinB (but not with ankyrinG) are involved in the initial formation of neurites. In the membranous protrusions surrounding the soma before neuritogenesis, filamentous actin (F-actin) and ankyrinB continuously move toward the soma (retrograde flow). Bead-tracking experiments show that ankyrinB mediates L1-CAM coupling with retrograde F-actin flow in these perisomatic structures. Ligation of the L1-CAM ectodomain by an immobile substrate induces L1CD-ankyrinB binding and the formation of stationary ankyrinB clusters. Neurite initiation preferentially occurs at the site of these clusters. In contrast, ankyrinB is involved neither in L1-CAM coupling with F-actin flow in growth cones nor in L1-based neurite elongation. Our results indicate that ankyrinB promotes neurite initiation by acting as a component of the clutch module that transmits traction force generated by F-actin flow to the extracellular substrate via L1-CAM.

    The Journal of cell biology 2003;163;5;1077-88

  • The L1CAM extracellular region: a multi-domain protein with modular and cooperative binding modes.

    Haspel J and Grumet M

    W.M. Keck Center for Collaborative Neuroscience and Dept. of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ 08854-8082, USA.

    L1CAM is a neural cell adhesion molecule (CAM) that is critical for proper CNS development in humans. It mediates a myriad of activities important to CNS maturation, including neurite outgrowth, adhesion, fasciculation, migration, myelination and axon guidance. L1CAM promotes these cellular activities by interacting with a diverse group of CAMs, extracellular matrix molecules and signaling receptors through interactions involving its extracellular region. This region is composed of 11 tandem immunoglobulin-like (Ig) domains. This review focuses on the L1CAM extracellular region, and how recent work has clarified important aspects of its structure and function. These studies have provided new insights into how L1CAM binds to several different extracellular molecules, how these binding activities are regulated, and how L1CAM initially folds. Furthermore, these studies suggest that the extracellular region is a dynamic, integrated structure that depends on cooperative interactions among its Ig-like domains for proper functioning.

    Frontiers in bioscience : a journal and virtual library 2003;8;s1210-25

  • CRMP-2 regulates polarized Numb-mediated endocytosis for axon growth.

    Nishimura T, Fukata Y, Kato K, Yamaguchi T, Matsuura Y, Kamiguchi H and Kaibuchi K

    Department of Cell Pharmacology, Graduate School of Medicine, Nagoya University, 65 Tsurumai, Showa, Nagoya, Aichi 466-8550, Japan.

    Axon growth during neural development is highly dependent on both cytoskeletal re-organization and polarized membrane trafficking. Previously, we demonstrated that collapsin response mediator protein-2 (CRMP-2) is critical for specifying axon/dendrite fate and axon growth in cultured hippocampal neurons, possibly by interacting with tubulin heterodimers and promoting microtubule assembly. Here, we identify Numb as a CRMP-2-interacting protein. Numb has been shown to interact with alpha-adaptin and to be involved in endocytosis. We found that Numb was associated with L1, a neuronal cell adhesion molecule that is endocytosed and recycled at the growth cone, where CRMP-2 and Numb were colocalized. Furthermore, expression of dominant-negative CRMP-2 mutants or knockdown of CRMP-2 message with small-interfering (si) RNA inhibited endocytosis of L1 at axonal growth cones and suppressed axon growth. These results suggest that in addition to regulating microtubule assembly, CRMP-2 is involved in polarized Numb-mediated endocytosis of proteins such as L1.

    Nature cell biology 2003;5;9;819-26

  • Gene diversity patterns at 10 X-chromosomal loci in humans and chimpanzees.

    Kitano T, Schwarz C, Nickel B and Pääbo S

    Department of Evolutionary Genetics, Max-Planck-Institute for Evolutionary Anthropology, Leipzig, Germany.

    We have investigated the pattern and extent of nucleotide diversity in 10 X-chromosomal genes where mutations are known to cause mental retardation in humans. For each gene, we sequenced the entire coding region from cDNA in humans, chimpanzees, and orangutans, as well as about 3 kb of genomic DNA in 20 humans sampled worldwide and in 10 chimpanzees representing two "subspecies." Overall nucleotide diversity in these genes is about twofold lower in humans than in chimpanzees, and nucleotide diversity within and between species is low, suggesting that a high level of functional constraint acts on these genes. Strikingly, we find that a summary of the allele frequency spectrum is significantly correlated in humans and chimpanzees, perhaps reflecting very similar levels of constraint at these genes in the two species. A possible exception is FMR2, which shows a higher number of nonsynonymous than synonymous substitutions on the human lineage, suggesting the action of positive selection.

    Molecular biology and evolution 2003;20;8;1281-9

  • The immunoglobulin-superfamily molecule basigin is a binding protein for oligomannosidic carbohydrates: an anti-idiotypic approach.

    Heller M, von der Ohe M, Kleene R, Mohajeri MH and Schachner M

    Department of Neurobiology, Swiss Federal Institute of Technology, Zürich, Switzerland.

    Recognition molecules that carry carbohydrate structures regulate cell interactions during development and play important roles in synaptic plasticity and regeneration in the adult. Glycans appear to be involved in these interactions. We have searched for binding proteins for oligomannosidic structures using the L3 antibody directed against high mannose-type glycans in an anti-idiotypic approach. A selected monoclonal anti-idiotype antibody was used for affinity chromatography and identified basigin as a binding protein from mouse brain detergent lysates. Basigin was found to bind to high mannose-carrying cell recognition molecules, such as myelin-associated glycoprotein, L1, the beta2-subunit of Na+/K+-ATPase and an oligomannosidic neoglycolipid. Furthermore, basigin was involved in outgrowth of astrocytic processes in vitro. A striking homology between the first immunoglobulin (Ig)-like domain of basigin and the fourth Ig-like domain of NCAM, previously shown to bind to oligomannosidic glycans, and the lectin domain of the mannose receptor confirms that basigin is an oligomannose binding lectin. To our knowledge this is the first report that anti-idiotypic antibodies can be used to identify binding partners for carbohydrates.

    Journal of neurochemistry 2003;84;3;557-65

  • L1 adhesion molecule (CD 171) in development and progression of human malignant melanoma.

    Fogel M, Mechtersheimer S, Huszar M, Smirnov A, Abu-Dahi A, Tilgen W, Reichrath J, Georg T, Altevogt P and Gutwein P

    Department of Pathology, Kaplan Hospital, Rehovot, Israel.

    The L1 adhesion molecule (CD171) plays an important role in axon guidance and cell migration in the nervous system. In the human, L1 is expressed on tumors derived from neurocrest and on certain carcinomas. We have analyzed immunohistochemically L1 expression on paraffin embedded specimens of acquired melanocytic nevi, primary cutaneous melanomas, and cutaneous and lymph node metastases of malignant melanomas. We found an increase in L1 immunoreactivity in malignant melanomas and metastases of malignant melanomas as compared to acquired melanocytic nevi that was statistically significant (P<0.05). Additionally, a correlation of L1 immunoreactivity with histological data of prognostic value such as Clark level and the expression of alphav-integrins was found. We detected soluble L1 in the conditioned medium of cultivated melanoma cells but only in 1/40 serum samples from a panel of melanoma patients representing various stages of disease. Our findings suggest that the presence of L1 might contribute to tumor progression by promoting cell adhesion and migration.

    Cancer letters 2003;189;2;237-47

  • X-linked hydrocephalus: another two families with an L1 mutation.

    Rodríguez Criado G, Pérez Aytés A, Martínez F, Vos YJ, Verlind E, González-Meneses López A, Gómez de Terreros Sánchez I and Schrander-Stumpel C

    Unidad de Dismorfología, H.I.U.V. Rocío, Sevilla, Spain.

    X-linked hydrocephalus is a variable condition caused by mutations in the gene encoding for L1CAM. This gene is located at Xq28. Clinically the spectrum ranges from males with lethal congenital hydrocephalus to mild/moderate mental retardation and spastic paraplegia. Few carrier females show minimal signs of the syndrome. Although most cases are familial, de novo situations have been reported. We report two new families with the syndrome and a L1 mutation. Family 1 has two patients and family 2 a single patient. Clinical diagnosis in all three affected boys was beyond doubt. Prenatal testing through chorionic villus biopsy is possible only with a demonstrated L1 mutation. In lethal sporadic cases neuropathology is very important in order to evaluate for features of the syndrome. We stress the importance of further clinical reports including data on neuropathology and DNA analysis in order to further understand the mechanisms involved in this disorder.

    Genetic counseling (Geneva, Switzerland) 2003;14;1;57-65

  • Nucleotide variability at G6pd and the signature of malarial selection in humans.

    Saunders MA, Hammer MF and Nachman MW

    Department of Ecology and Evolutionary Biology, University of Arizona, Tucson, Arizona 85721, USA. msaunder@u.arizona.edu

    Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common enzymopathy in humans. Deficiency alleles for this X-linked disorder are geographically correlated with historical patterns of malaria, and the most common deficiency allele in Africa (G6PD A-) has been shown to confer some resistance to malaria in both hemizygous males and heterozygous females. We studied DNA sequence variation in 5.1 kb of G6pd from 47 individuals representing a worldwide sample to examine the impact of selection on patterns of human nucleotide diversity and to infer the evolutionary history of the G6PD A- allele. We also sequenced 3.7 kb of a neighboring locus, L1cam, from the same set of individuals to study the effect of selection on patterns of linkage disequilibrium. Despite strong clinical evidence for malarial selection maintaining G6PD deficiency alleles in human populations, the overall level of nucleotide heterozygosity at G6pd is typical of other genes on the X chromosome. However, the signature of selection is evident in the absence of genetic variation among A- alleles from different parts of Africa and in the unusually high levels of linkage disequilibrium over a considerable distance of the X chromosome. In spite of a long-term association between Plasmodium falciparum and the ancestors of modern humans, patterns of nucleotide variability and linkage disequilibrium suggest that the A- allele arose in Africa only within the last 10,000 years and spread due to selection.

    Genetics 2002;162;4;1849-61

  • X-linked hydrocephalus: a novel missense mutation in the L1CAM gene.

    Sztriha L, Vos YJ, Verlind E, Johansen J and Berg B

    Department of Pediatrics, Faculty of Medicine and Health Sciences, United Arab Emirates University, Al Ain.

    X-linked hydrocephalus is associated with mutations in the L1 neuronal cell adhesion molecule gene. L1 protein plays a key role in neurite outgrowth, axonal guidance, and pathfinding during the development of the nervous system. A male is described with X-linked hydrocephalus who had multiple small gyri, hypoplasia of the white matter, agenesis of the corpus callosum, and lack of cleavage of the thalami. Scanning the L1 neuronal cell adhesion molecule gene in Xq28 revealed a novel missense mutation: transition of a guanine to cytosine at position 1,243, which led to conversion of alanine to proline at position 415 in the Ig 4 domain of the L1 protein. It is likely that the X-linked hydrocephalus and cerebral dysgenesis are a result of the abnormal structure and function of the mutant L1 protein.

    Pediatric neurology 2002;27;4;293-6

  • Analysis of interactions of the adhesion molecule TAG-1 and its domains with other immunoglobulin superfamily members.

    Pavlou O, Theodorakis K, Falk J, Kutsche M, Schachner M, Faivre-Sarrailh C and Karagogeos D

    Department of Basic Science, University of Crete Medical School and Institute of Molecular Biology and Biotechnology, P.O. Box 1527, Heraklion, Greece.

    Cell adhesion molecules of the immunoglobulin superfamily promote cell aggregation and neurite outgrowth via homophilic and heterophilic interactions. The transient axonal glycoprotein TAG-1 induces cell aggregation through homophilic interaction of its fibronectin repeats. We investigated the domains responsible for the neurite outgrowth promoting activity of TAG-1 as well as its interactions with other cell adhesion molecules. Binding experiments with Fc-chimeric proteins revealed that TAG-1 interacts with L1, NrCAM, and F3/contactin. The membrane-associated as opposed to the soluble form of TAG-1 behaves differently in these assays. We demonstrate that both the immunoglobulin as well as the fibronectin domains promote neurite outgrowth when used as substrates. Furthermore we investigated the putative role of L1 and NrCAM as the neuronal TAG-1 receptors mediating neurite extension. DRG neurons from L1-deficient mice were found to extend neurites on TAG-1 substrates and blocking NrCAM function did not diminish the TAG-1-dependent neurite outgrowth. These results indicate that neither L1 nor NrCAM are required for TAG-1-elicited neurite outgrowth.

    Molecular and cellular neurosciences 2002;20;3;367-81

  • Functional binding interaction identified between the axonal CAM L1 and members of the ERM family.

    Dickson TC, Mintz CD, Benson DL and Salton SR

    Fishberg Research Center for Neurobiology, The Mount Sinai School of Medicine, New York, NY 10029, USA.

    A yeast two-hybrid library was screened using the cytoplasmic domain of the axonal cell adhesion molecule L1 to identify binding partners that may be involved in the regulation of L1 function. The intracellular domain of L1 bound to ezrin, a member of the ezrin, radixin, and moesin (ERM) family of membrane-cytoskeleton linking proteins, at a site overlapping that for AP2, a clathrin adaptor. Binding of bacterial fusion proteins confirmed this interaction. To determine whether ERM proteins interact with L1 in vivo, extracellular antibodies to L1 were used to force cluster the protein on cultured hippocampal neurons and PC12 cells, which were then immunolabeled for ERM proteins. Confocal analysis revealed a precise pattern of codistribution between ERMs and L1 clusters in axons and PC12 neurites, whereas ERMs in dendrites and spectrin labeling remained evenly distributed. Transfection of hippocampal neurons grown on an L1 substrate with a dominant negative ERM construct resulted in extensive and abnormal elaboration of membrane protrusions and an increase in axon branching, highlighting the importance of the ERM-actin interaction in axon development. Together, our data indicate that L1 binds directly to members of the ERM family and suggest this association may coordinate aspects of axonal morphogenesis.

    Funded by: NCRR NIH HHS: S10 RR0 9145; NIAAA NIH HHS: AA12971, R01 AA014898, R21 AA012971, R21 AA012971-01, R21 AA012971-02, R21 AA012971-03

    The Journal of cell biology 2002;157;7;1105-12

  • Hirschsprung disease and L1CAM: is the disturbed sex ratio caused by L1CAM mutations?

    Hofstra RM, Elfferich P, Osinga J, Verlind E, Fransen E, López Pisón J, de Die-Smulders CE, Stolte-Dijkstra I and Buys CH

    Journal of medical genetics 2002;39;3;E11

  • Hydrocephalus and intestinal aganglionosis: is L1CAM a modifier gene in Hirschsprung disease?

    Parisi MA, Kapur RP, Neilson I, Hofstra RM, Holloway LW, Michaelis RC and Leppig KA

    Division of Genetics and Development, Department of Pediatrics, University of Washington and Children's Hospital and Regional Medical Center, Seattle, Washington 98105, USA. mparisi@u.washington.edu

    Congenital hydrocephalus associated with aqueductal stenosis and/or agenesis of the corpus callosum has been described in newborn males with mutations in L1CAM, a gene that encodes a neural cell adhesion molecule. These males usually have severe mental retardation and may have spastic paraplegia and adducted thumbs. In contrast, Hirschsprung disease, or absence of ganglion cells in the distal gut, has rarely been described in such individuals. We report a male infant who had severe hydrocephalus identified in the prenatal period with evidence of aqueductal stenosis and adducted thumbs at birth. He developed chronic constipation, and rectal biopsy confirmed the diagnosis of Hirschsprung disease. Molecular testing of the L1CAM gene revealed a G2254A mutation, resulting in a V752M amino acid substitution. A common polymorphism in RET, but no mutation, was identified. Our patient represents the third example of coincident hydrocephalus and Hirschsprung disease in an individual with an identified L1CAM mutation. We hypothesize that L1CAM-mediated cell adhesion may be important for the ability of ganglion cell precursors to populate the gut, and that L1CAM may modify the effects of a Hirschsprung disease-associated gene to cause intestinal aganglionosis.

    Funded by: NICHD NIH HHS: P30-HD28834; NIDDK NIH HHS: R01-DK52530

    American journal of medical genetics 2002;108;1;51-6

  • L1 cell adhesion molecule signal cascades: targets for ethanol developmental neurotoxicity.

    Bearer CF

    Department of Pediatrics and Neurosciences, Case Western Reserve University, Cleveland, OH 44106, USA. cfb3@po.cwru.edu

    A major mechanism guiding neural development is through cell-cell and cell-matrix adhesions and signaling mediated by cell adhesion molecules (CAMs). The majority of CAMs have been grouped into three families: the cadherins, the integrins and the members of the immunoglobulin superfamily including L1. While the elucidation of new receptors and matrix components has become a frequent occurrence, the elucidation of the mechanisms by which they operate, and the function of those mechanisms in complex developmental events remains rudimentary. Members of all three families participate in differential adhesion, signal transduction and physical/mechanical effects. Each of these modes of action is a potential target for developmental neurotoxicants. In this brief review, the role of L1 in normal and abnormal neurodevelopment will be summarized. L1 is a cell surface transmembrane glycoprotein with a single copy gene on the X chromosome. There are two alternatively spliced exons, with the RSLE containing form found only on axons and growth cones of post-mitotic neurons. L1 mediates the following functions: adhesion, neurite extension, neuronal migration, and axon fasciculation. L1 is critical for normal neural development; humans with genetic defects in L1, termed corpus callosum hypoplasia, mental retardation, adducted thumbs, spasticity and hydrocephalus (CRASH) syndrome, and mice lacking expression of L1 have extensive neuropathologic and aberrant behaviors. The observation that patients with fetal alcohol syndrome share similar features to patients with CRASH has lead to the investigation of the effects of ethanol on L1. Physiologic concentrations of ethanol have been shown to inhibit L1 mediated neurite outgrowth in cerebellar granule neurons. Such inhibition may result from decreased expression, altered cell surface distribution, impaired signal transduction, or impaired interaction with the cytoskeleton. These data indicate that L1 and its associated signaling pathways are potentially targets for developmental neurotoxicants.

    Neurotoxicology 2001;22;5;625-33

  • Cytoplasmic domain mutations of the L1 cell adhesion molecule reduce L1-ankyrin interactions.

    Needham LK, Thelen K and Maness PF

    Department of Biochemistry, School of Medicine, University of North Carolina, Chapel Hill, North Carolina 27599-7260, USA.

    The neural adhesion molecule L1 mediates the axon outgrowth, adhesion, and fasciculation that are necessary for proper development of synaptic connections. L1 gene mutations are present in humans with the X-linked mental retardation syndrome CRASH (corpus callosum hypoplasia, retardation, aphasia, spastic paraplegia, hydrocephalus). Three missense mutations associated with CRASH syndrome reside in the cytoplasmic domain of L1, which contains a highly conserved binding region for the cytoskeletal protein ankyrin. In a cellular ankyrin recruitment assay that uses transfected human embryonic kidney (HEK) 293 cells, two of the pathologic mutations located within the conserved SFIGQY sequence (S1224L and Y1229H) strikingly reduced the ability of L1 to recruit 270 kDa ankyrinG protein that was tagged with green fluorescent protein (ankyrin-GFP) to the plasma membrane. In contrast, the L1 missense mutation S1194L and an L1 isoform lacking the neuron-specific sequence RSLE in the cytoplasmic domain were as effective as RSLE-containing neuronal L1 in the recruitment of ankyrin-GFP. Ankyrin binding by L1 was independent of cell-cell interactions. Receptor-mediated endocytosis of L1 regulates intracellular signal transduction, which is necessary for neurite outgrowth. In rat B35 neuroblastoma cell lines stably expressing L1 missense mutants, antibody-induced endocytosis was unaffected by S1224L or S1194L mutations but appeared to be enhanced by the Y1229H mutation. These results suggested a critical role for tyrosine residue 1229 in the regulation of L1 endocytosis. In conclusion, specific mutations within key residues of the cytoplasmic domain of L1 (Ser(1224), Tyr(1229)) destabilize normal L1-ankyrin interactions and may influence L1 endocytosis to contribute to the mechanism of neuronal dysfunction in human X-linked mental retardation.

    Funded by: NIAAA NIH HHS: AA 11605; NICHD NIH HHS: HD 35170; NINDS NIH HHS: NS 26620

    The Journal of neuroscience : the official journal of the Society for Neuroscience 2001;21;5;1490-500

  • Genetic and clinical aspects of X-linked hydrocephalus (L1 disease): Mutations in the L1CAM gene.

    Weller S and Gärtner J

    Department of Pediatrics, Heinrich Heine University, Düsseldorf, Germany.

    L1 disease is a group of overlapping clinical phenotypes including X-linked hydrocephalus, MASA syndrome, spastic paraparesis type 1, and X-linked agenesis of corpus callosum. The patients are characterized by hydrocephalus, agenesis or hypoplasia of corpus callosum and corticospinal tracts, mental retardation, spastic paraplegia, and adducted thumbs. The responsible gene, L1CAM, encodes the L1 protein which is a member of the immunoglobulin superfamily of neuronal cell adhesion molecules. The L1 protein is expressed in neurons and Schwann cells and seems to be essential for nervous system development and function. The patients' gene mutations are distributed over the functional protein domains. The exact mechanisms by which these mutations cause a loss of L1 protein function are unknown. There appears to be a relationship between the patients' clinical phenotype and the genotype. Missense mutations in extracellular domains or mutations in cytoplasmic regions cause milder phenotypes than those leading to truncation in extracellular domains or to non-detectable L1 protein. Diagnosis of patients and carriers, including prenatal testing, is based on the characteristic clinical picture and DNA mutation analyses. At present, there is no therapy for the prevention or cure of patients' neurological disabilities.

    Human mutation 2001;18;1;1-12

  • Identification of single-nucleotide polymorphisms (SNPs) of human N-acetyltransferase genes NAT1, NAT2, AANAT, ARD1 and L1CAM in the Japanese population.

    Sekine A, Saito S, Iida A, Mitsunobu Y, Higuchi S, Harigae S and Nakamura Y

    SNP Research Center, Institute of Physical and Chemical Research, Tokyo, Japan.

    By direct sequencing of regions of the human genome containing five genes belonging to the acetyltransferase family, arylamine N-acetyltransferase (NAT1), arylamine N-acetyltransferase (NAT2), arylalkylamine N-acetyltransferase (AANAT), L1 cell adhesion molecule (L1CAM), and the human homolog of Saccharomyces cerevisiae N-acetyltransferase ARD1, we identified 53 single-nucleotide polymorphisms (SNPs) and two insertion/ deletion polymorphisms in 48 healthy Japanese volunteers. NAT1 and NAT2 are so-called drug-metabolizing enzymes. In the NAT1 gene we found two SNPs and a 3-bp insertion/ deletion polymorphism that corresponded to the NAT1*3, *10, and *18A/*18B alleles reported in other populations. The frequencies of NAT1* alleles in our Japanese subjects were 52.6% for NAT1*4, 1.0% for NAT1*3, 40.6% for NAT1*10, 2.6% for NAT1*18A and 3.1% for NAT1*18B. In the NAT2 gene we found 32 SNPs and a 1-bp insertion/ deletion polymorphism; 6 SNPs within the coding region were reported previously and belonged to the slow acetylator group (NAT2*5, NAT2*6 and NAT2*7), and 2 of the 8 SNPs in the 5' flanking region were reported in the dbSNP of GenBank, but the remaining 24 SNPs and the insertion/deletion polymorphism were novel. The frequencies of NAT2* alleles in Japanese (51.3% for NAT2*4, 1.6% for *5B, 26.1% for *6A, 2.2% for *6B, 1.2% for *7A, 10.1% for *7B, 7.4% for *12A, and 1.1% for *13) were significantly different from those reported in Caucasian populations. In the AANAT gene we found 4 novel SNPs: 2 in the 5' flanking region, 1 in exon 4, and 1 in intron 3. In the two genes belonging to the N-terminal N-acetyltransferase family, we identified 9 SNPs, 7 of them novel, for ARD1, and six novel SNPs for L1CAM. Variations at these loci may contribute to an understanding of the way in which different genotypes may affect the activities of human N-acetyltransferases, especially as regards the therapeutic efficacy of certain drugs and antibiotics.

    Journal of human genetics 2001;46;6;314-9

  • Characterization of the L1-neurocan-binding site. Implications for L1-L1 homophilic binding.

    Oleszewski M, Gutwein P, von der Lieth W, Rauch U and Altevogt P

    Tumor Immunology Programme, G0100, German Cancer Research Center, D-69120 Heidelberg, Germany.

    The L1 adhesion molecule is a 200-220-kDa membrane glycoprotein of the Ig superfamily implicated in important neural processes including neuronal cell migration, axon outgrowth, learning, and memory formation. L1 supports homophilic L1-L1 binding that involves several Ig domains but can also bind with high affinity to the proteoglycan neurocan. It has been reported that neurocan can block homophilic binding; however, the mechanism of inhibition and the precise binding sites in both molecules have not been determined. By using fusion proteins, site-directed mutagenesis, and peptide blocking experiments, we have characterized the neurocan-binding site in the first Ig-like domain of human L1. Results from molecular modeling suggest that the sequences involved in neurocan binding are localized on the surface of the first Ig domain and largely overlap with the G-F-C beta-strands proposed to interact with the fourth Ig domain during homophilic binding. This suggests that neurocan may sterically hinder a proper alignment of L1 domains. We find that the C-terminal portion of neurocan is sufficient to mediate binding to the first Ig domain of L1, and we suggest that the sushi domain cooperates with a glycosaminoglycan side chain in forming the binding site for L1.

    The Journal of biological chemistry 2000;275;44;34478-85

  • Plasmin-sensitive dibasic sequences in the third fibronectin-like domain of L1-cell adhesion molecule (CAM) facilitate homomultimerization and concomitant integrin recruitment.

    Silletti S, Mei F, Sheppard D and Montgomery AM

    Department of Pediatrics, University of California at San Diego, La Jolla, California 92037, USA.

    L1 is a multidomain transmembrane neural recognition molecule essential for neurohistogenesis. While moieties in the immunoglobulin-like domains of L1 have been implicated in both heterophilic and homophilic binding, the function of the fibronectin (FN)-like repeats remains largely unresolved. Here, we demonstrate that the third FN-like repeat of L1 (FN3) spontaneously homomultimerizes to form trimeric and higher order complexes. Remarkably, these complexes support direct RGD-independent interactions with several integrins, including alpha(v)beta(3) and alpha(5)beta(1). A pep- tide derived from the putative C-C' loop of FN3 (GSQRKHSKRHIHKDHV(852)) also forms trimeric complexes and supports alpha(v)beta(3) and alpha(5)beta(1) binding. Substitution of the dibasic RK(841) and KR(845) sequences within this peptide or the FN3 domain limited multimerization and abrogated integrin binding. Evidence is presented that the multimerization of, and integrin binding to, the FN3 domain is regulated both by conformational constraints imposed by other domains and by plasmin- mediated cleavage within the sequence RK( downward arrow)HSK( downward arrow)RH(846). The integrin alpha(9)beta(1), which also recognizes the FN3 domain, colocalizes with L1 in a manner restricted to sites of cell-cell contact. We propose that distal receptor ligation events at the cell-cell interface may induce a conformational change within the L1 ectodomain that culminates in receptor multimerization and integrin recruitment via interaction with the FN3 domain.

    Funded by: NCI NIH HHS: F32 CA072192, R01 CA069112, R01 CA69112-01; NHLBI NIH HHS: R01 HL62477-01

    The Journal of cell biology 2000;149;7;1485-502

  • Spectrum and detection rate of L1CAM mutations in isolated and familial cases with clinically suspected L1-disease.

    Finckh U, Schröder J, Ressler B, Veske A and Gal A

    Department of Human Genetics, University Hospital Eppendorf, University of Hamburg, Hamburg, Germany.

    Mutations in L1CAM, the gene encoding the L1 neuronal cell adhesion molecule, lead to an X-linked trait characterized by one or more of the symptoms of hydrocephalus, adducted thumbs, agenesis or hypoplasia of corpus callosum, spastic paraplegia, and mental retardation (L1-disease). We screened 153 cases with prenatally or clinically suspected X-chromosomal hydrocephalus for L1CAM mutations by SSCP analysis of the 28 coding exons and regulatory elements in the 5'-untranslated region of the gene. Forty-six pathogenic mutations were found (30.1% detection rate), the majority consisting of nonsense, frameshift, and splice site mutations. In eight cases, segregation analysis disclosed recent de novo mutations. Statistical analysis of the data indicates a significant effect on mutation detection rate of (i) family history, (ii) number of L1-disease typical clinical findings, and (iii) presence or absence of signs not typically associated with L1CAM-disease. Whereas mutation detection rate was 74.2% for patients with at least two additional cases in the family, only 16 mutations were found in the 102 cases with negative family history (15.7% detection rate). Our data suggest a higher than previously assumed contribution of L1CAM mutations in the pathogenesis of the heterogeneous group of congenital hydrocephalus.

    American journal of medical genetics 2000;92;1;40-6

  • Novel missense mutation in the L1 gene in a child with corpus callosum agenesis, retardation, adducted thumbs, spastic paraparesis, and hydrocephalus.

    Sztriha L, Frossard P, Hofstra RM, Verlind E and Nork M

    Department of Pediatrics, Faculty of Medicine and Health Sciences, United Arab Emirates University. sztriha@uaeu.ac.ae

    Corpus callosum agenesis, retardation, adducted thumbs, spastic paraparesis, and hydrocephalus (CRASH syndrome) is an X-linked recessive disorder caused by mutations in the neuronal cell adhesion molecule L1 (LICAM) gene. L1 plays a key role in axon outgrowth and pathfinding during the development of the nervous system. We describe the case of a boy from the United Arab Emirates who presented with CRASH syndrome. Scanning the L1 gene of the patient resulted in the discovery of a novel missense mutation: transition of a G (guanine) to T (thymine) at position 604 (G604-->T), which results in conversion of aspartic acid to tyrosine at position 202 (D202Y) of the L1 protein. It is very likely that the cerebral dysgenesis is due to the abnormal structure and function of L1.

    Journal of child neurology 2000;15;4;239-43

  • Homophilic NCAM interactions interfere with L1 stimulated neurite outgrowth.

    Kristiansen LV, Marques FA, Soroka V, Ronn LC, Kiselyov V, Pedersen N, Berezin V and Bock E

    Protein Laboratory, Institute of Molecular Pathology, University of Copenhagen, Panum Institute, Blegdamsvej 3C, Bld. 6.2, DK-2200, Copenhagen N, Denmark.

    The cell adhesion molecules NCAM and L1 are considered to play key roles in neuronal development and plasticity. L1 has been shown to interact with NCAM, possibly through NCAM binding to oligomannosidic glycans present in L1. We investigated the effect of recombinant immunoglobulin (Ig) modules of NCAM involved in homophilic NCAM binding, on L1 induced neurite outgrowth from PC12-E2 cells and found a complete inhibition of L1 induced neurite outgrowth after addition of Ig-modules 1, 2 and 3 of NCAM, suggesting that the ligation state of NCAM is crucial for normal L1 signaling.

    FEBS letters 1999;464;1-2;30-4

  • Anti-neuroblastoma antibody chCE7 binds to an isoform of L1-CAM present in renal carcinoma cells.

    Meli ML, Carrel F, Waibel R, Amstutz H, Crompton N, Jaussi R, Moch H, Schubiger PA and Novak-Hofer I

    Center for Radiopharmaceutical Sciences, Paul Scherrer Institute, Villigen-PSI, Switzerland.

    Immunoprecipitation after cell surface labeling of human neuroblastoma cells showed that the anti-neuroblastoma monoclonal antibody (mAb) chCE7 binds to a 200,000 M(r) cell surface protein. The protein was partially purified by immuno-affinity chromatography from a human renal carcinoma and a human neuroblastoma cell line, which both showed high levels of binding of MAb chCE7. NH(2)-terminal sequences of 18 and 15 amino acid residues were determined. Both sequences isolated from the renal carcinoma and the neuroblastoma cells showed strong homology to human cell adhesion molecule L1 (L1-CAM), and both were characterized by the NH(2)-terminal deletion of 5 amino acids, comprising exon 2 of L1-CAM. Reverse trancription-polymerase chain reaction (RT-PCR) analysis of the regions spanning exon 2 and exon 27 of L1-CAM indicated that in neuroblastoma cells both transcripts for the full-length and exon-deleted forms are present, whereas in the renal carcinoma cell lines only the exon-deleted L1-CAM isoform were detected. Western blot analysis showed that 6 of 7 tested renal carcinoma cell lines and 5 of 15 renal carcinoma tissues expressed L1-CAM. In normal adult kidney tissue, very low levels of protein expression were found. Northern blot analysis confirmed that in renal carcinoma and neuroblastoma cell lines L1-CAM mRNA levels are correlated with protein expression.

    International journal of cancer 1999;83;3;401-8

  • Cis-activation of L1-mediated ankyrin recruitment by TAG-1 homophilic cell adhesion.

    Malhotra JD, Tsiotra P, Karagogeos D and Hortsch M

    Department of Anatomy and Cell Biology, University of Michigan, Ann Arbor, Michigan 48109-0616, USA.

    Neural cell adhesion molecules (CAMs) of the immunoglobulin (Ig) superfamily mediate not only cell aggregation but also growth cone guidance and neurite outgrowth. In this study we demonstrate that two neural CAMs, L1-CAM and TAG-1, induce the homophilic aggregation of Drosophila S2 cells but are unable to interact with each other when expressed on different cells (trans-interaction). However, immunoprecipitations from cells co-expressing L1-CAM and TAG-1 showed a strong cis-interaction between the two molecules in the plane of the plasma membrane. TAG-1 is linked to the membrane by a glycosylphosphatidylinositol (GPI) anchor and therefore is unable to directly interact with cytoplasmic proteins. In contrast, L1-CAM-mediated homophilic cell adhesion induces the selective recruitment of the membrane skeleton protein ankyrin to areas of cell contact. Immunolabeling experiments in which S2 cells expressing TAG-1 were mixed with cells co-expressing L1-CAM and TAG-1 demonstrated that the homophilic interaction between TAG-1 molecules results in the cis-activation of L1-CAM to bind ankyrin. This TAG-1-dependent recruitment of the membrane skeleton provides an example of how GPI-anchored CAMs are able to transduce signals to the cytoplasm. Furthermore, such interactions might ultimately result in the recruitment and the activation of other signaling molecules at sites of cell contacts.

    Funded by: NICHD NIH HHS: HD29388

    The Journal of biological chemistry 1998;273;50;33354-9

  • Nervous system defects of AnkyrinB (-/-) mice suggest functional overlap between the cell adhesion molecule L1 and 440-kD AnkyrinB in premyelinated axons.

    Scotland P, Zhou D, Benveniste H and Bennett V

    Howard Hughes Medical Institute, Departments of Cell Biology, Duke University Medical Center, Durham, North Carolina 27710, USA.

    The L1 CAM family of cell adhesion molecules and the ankyrin family of spectrin-binding proteins are candidates to collaborate in transcellular complexes used in diverse contexts in nervous systems of vertebrates and invertebrates. This report presents evidence for functional coupling between L1 and 440-kD ankyrinB in premyelinated axons in the mouse nervous system. L1 and 440-kD ankyrinB are colocalized in premyelinated axon tracts in the developing nervous system and are both down-regulated after myelination. AnkyrinB (-/-) mice exhibit a phenotype similar to, but more severe, than L1 (-/-) mice and share features of human patients with L1 mutations. AnkyrinB (-/-) mice exhibit hypoplasia of the corpus callosum and pyramidal tracts, dilated ventricles, and extensive degeneration of the optic nerve, and they die by postnatal day 21. AnkyrinB (-/-) mice have reduced L1 in premyelinated axons of long fiber tracts, including the corpus callosum, fimbria, and internal capsule in the brain, and pyramidal tracts and lateral columns of the spinal cord. L1 was evident in the optic nerve at postnatal day 1 but disappeared by postnatal day 7 in mutant mice while NCAM was unchanged. Optic nerve axons of ankyrinB (-/-) mice become dilated with diameters up to eightfold greater than normal, and they degenerated by day 20. These findings provide the first evidence for a role of ankyrinB in the nervous system and support an interaction between 440-kD ankyrinB and L1 that is essential for maintenance of premyelinated axons in vivo.

    Funded by: NCRR NIH HHS: P41 RR005959, P41RR05959

    The Journal of cell biology 1998;143;5;1305-15

  • The site of a missense mutation in the extracellular Ig or FN domains of L1CAM influences infant mortality and the severity of X linked hydrocephalus.

    Michaelis RC, Du YZ and Schwartz CE

    Center for Molecular Studies, J C Self Research Institute, Greenwood Genetic Center, SC 29646, USA.

    The L1 cell adhesion molecule (L1CAM) plays an important role in axon growth, fasciculation, and neural migration. Mutations in the L1CAM gene produce a phenotype characterised by X linked hydrocephalus, mental retardation, spastic paraplegia, adducted thumbs, and agenesis of the corpus callosum. We have conducted a detailed analysis of the phenotypic effects of missense mutations in the extracellular portion of L1CAM, following a study that differentiated between "key" amino acid residues critical for maintaining the conformation of the extracellular immunoglobulin type C-like (Ig) or fibronectin type III-like (FN) domains and surface residues of less certain significance. We have analysed the data from 71 published cases and seven patients whose mutations were detected in our laboratory to determine if the site of a missense mutation in the Ig or FN domains correlated with the severity of hydrocephalus, presence of adducted thumbs, or survival past infancy. Mutations affecting the key residues in either type of domain were more likely to produce a phenotype with severe hydrocephalus, adducted thumbs, and lifespan less than one year than were mutations affecting surface residues. In addition, mutations affecting the FN domains were more likely than those affecting Ig domains to produce a phenotype with severe hydrocephalus, with less certain effects on adducted thumbs and lifespan. Mutations in key residues of the FN domains were particularly deleterious to infant survival. These data provide information that may be useful in predicting some aspects of the phenotypic effects of certain L1CAM mutations.

    Journal of medical genetics 1998;35;11;901-4

  • A neuronal form of the cell adhesion molecule L1 contains a tyrosine-based signal required for sorting to the axonal growth cone.

    Kamiguchi H and Lemmon V

    Department of Neurosciences, Case Western Reserve University, Cleveland, Ohio 44106, USA.

    The neural cell adhesion molecule L1, which is present on axons and growth cones, plays a crucial role in the formation of major axonal tracts such as the corticospinal tract and corpus callosum. L1 is preferentially transported to axons and inserted in the growth cone membrane. However, how L1 is sorted to axons remains unclear. Tyr1176 in the L1 cytoplasmic domain is adjacent to a neuron-specific alternatively spliced sequence, RSLE (Arg-Ser-Leu-Glu). The resulting sequence of YRSLE conforms to a tyrosine-based consensus motif (YxxL) for sorting of integral membrane proteins into specific cellular compartments. To study a possible role of the YRSLE sequence in L1 sorting, chick DRG neurons were transfected with human L1 cDNA that codes for full-length L1 (L1FL), a non-neuronal form of L1 that lacks the RSLE sequence (L1DeltaRSLE), mutant L1 with a Y1176A substitution (L1Y1176A), or L1 truncated immediately after the RSLE sequence (L1DeltaC77). L1FL and L1DeltaC77, both of which possess the YRSLE sequence, were expressed in the axonal growth cone and to a lesser degree in the cell body. In contrast, expression of both L1DeltaRSLE and L1Y1176A was restricted to the cell body and proximal axonal shaft. We also found that L1DeltaRSLE and L1Y1176A were integrated into the plasma membrane in the cell body after missorting. These data demonstrate that the neuronal form of L1 carries the tyrosine-based sorting signal YRSLE, which is critical for sorting L1 to the axonal growth cone.

    Funded by: NEI NIH HHS: EY-5285, R01 EY005285; NINDS NIH HHS: NS-34252

    The Journal of neuroscience : the official journal of the Society for Neuroscience 1998;18;10;3749-56

  • The neural cell adhesion molecule L1: genomic organisation and differential splicing is conserved between man and the pufferfish Fugu.

    Coutelle O, Nyakatura G, Taudien S, Elgar G, Brenner S, Platzer M, Drescher B, Jouet M, Kenwrick S and Rosenthal A

    Institute of Molecular Biotechnology, Department of Genome Analysis, Beutenbergstrasse 11, 07745, Jena, Germany.

    The human gene for the neural cell adhesion molecule L1 is located on Xq28 between the ALD and MeCP2 loci. Mutations in the L1 gene are associated with four related neurological disorders, X-linked hydrocephalus, spastic paraplegia (SPG1), MASA syndrome, and X-linked corpus callosum agenesis. The clinical relevance of L1 has led us to sequence the L1 gene in human and to investigate its conservation in the vertebrate model genome of the pufferfish, Fugu rubripes (Fugu), a species with a compact genome of around 40Mb. For this purpose we have sequenced a human and a Fugu cosmid clone containing the corresponding L1 genes. For comparison, we have also amplified and sequenced the complete Fugu L1 cDNA. We find that the genomic structure of L1 is conserved. The human and Fugu L1 gene both have 28 exons of nearly identical size. Differential splicing of exons 2 and 27 is conserved over 430 million years, the evolutionary time span between the teleost Fugu and the human L1 gene. In contrast to previously published Fugu genes, many introns are larger in the Fugu L1 gene, making it slightly larger in size despite the compact nature of the Fugu genome. Homology at the amino acid and the nucleotide level with 40% and 51%, respectively, is lower than that of any previously reported Fugu gene. At the level of protein structure, both human and Fugu L1 molecules are composed of six immunoglobulin (Ig)-like domains and five fibronectin (Fn) type III domains, followed by a transmembrane domain and a short cytoplasmic domain. Only the transmembrane and the cytoplasmic domains are significantly conserved in Fugu, supporting their proposed function in intracellular signalling and interaction with cytoskeletal elements in the process of neurite outgrowth and fascicle formation. Our results show that the cytoplasmic domain can be further subdivided into a conserved and a variable region, which may correspond to different functions. Most pathological missense mutations in human L1 affect conserved residues. Fifteen out of 22 reported missense mutations alter amino acids that are identical in both species.

    Gene 1998;208;1;7-15

  • Identification of novel L1CAM mutations using fluorescence-assisted mismatch analysis.

    Saugier-Veber P, Martin C, Le Meur N, Lyonnet S, Munnich A, David A, Hénocq A, Héron D, Jonveaux P, Odent S, Manouvrier S, Moncla A, Morichon N, Philip N, Satge D, Tosi M and Frébourg T

    Laboratoire de Génétique Moléculaire, CHU de Rouen, France.

    The L1CAM gene, which is located in Xq28 and codes for a neuronal cell adhesion molecule, is involved in three distinct conditions: HSAS (hydrocephalus-stenosis of the aqueduct of Sylvius), MASA (mental retardation, aphasia, shuffling gait, adductus thumbs), and SPG1 (spastic paraplegia). Molecular analysis of the L1CAM gene is labor-intensive because of the size of the coding region, which is fragmented in numerous exons, and because of the great allelic heterogeneity and distribution of the mutations. The FAMA (fluorescent assisted mismatch analysis) method combines the excellent sensitivity of the chemical cleavage method for scanning PCR fragments larger than 1 kb and the power of automated DNA sequencers. In order to optimize this method for L1CAM, we divided the gene into nine genomic fragments, each including three to four exons. These fragments were PCR-amplified using nine sets of primers containing additional rare universal sequences. A second-stage PCR, per formed with the two dye-labeled universal primers, allowed us to generate 1-kb-labeled fragments, which were then submitted to the chemical cleavage analysis. Among 12 French families with HSAS and/or MASA, we identified nine distinct L1CAM mutations, seven of which were novel, and an intronic variation. This study demonstrates that FAMA allows rapid and reliable detection of mutations in the L1CAM gene and thus represents one of the most appropriate methods to provide diagnosis for accurate genetic counseling in families with HSAS, MASA, or SPG1.

    Human mutation 1998;12;4;259-66

  • Multiple exon screening using restriction endonuclease fingerprinting (REF): detection of six novel mutations in the L1 cell adhesion molecule (L1CAM) gene.

    Du YZ, Srivastava AK and Schwartz CE

    J.C. Self Research Institute of Human Genetics, Greenwood Genetic Center, South Carolina 29646, USA.

    Restriction endonuclease fingerprinting (REF) has been utilized to screen 19 of the 28 exons in the L1CAM gene using only 5 PCR reactions. The clustered exons were amplified and the PCR products were subjected to endonuclease digestion and subsequent gel electrophoresis to produce a highly informative fingerprint for each PCR product. An alteration in the fingerprint, when compared to a control, determined the specific DNA fragment containing the mutation. Sequencing of the corresponding exon and flanking region was done to determine the precise location of the mutation. Using this method we have identified 6 novel mutations in the L1CAM gene in 5 patients with X-linked hydrocephalus and 2 patients with MASA. One of the mutations was common to both a patient with HSAS and a patient with MASA. The utilization of REF will allow for easier and quicker detection of mutations in the L1CAM gene. This method should be applicable for screening other genes with multiple, clustered exons.

    Human mutation 1998;11;3;222-30

  • Molecular analysis of the L1CAM gene in patients with X-linked hydrocephalus demonstrates eight novel mutations and suggests non-allelic heterogeneity of the trait.

    Gu SM, Orth U, Zankl M, Schröder J and Gal A

    Institut für Humangenetik, Universitäts-Krankenhaus Eppendorf, Hamburg, Germany.

    Eight novel mutations were identified in the gene encoding L1CAM, a neural cell adhesion protein, in patients/families with X-linked hydrocephalus (XHC) providing additional evidence for extreme allelic heterogeneity of the trait. The two nonsense mutations (Gln440Ter and Gln1042Ter) result most likely in functional null-alleles and complete absence of L1CAM at the cell surface. The four missense mutations (Leu482Pro, Ser542Pro, Met741Thr, and Val752Met) as well as delSer526 may considerably alter the structure of L1CAM. Interestingly, a missense mutation in an XHC family predicting the Val768Ile change in the second fibronectin type III domain of L1CAM was found not only in the two affected cousins and their obligate carrier mothers but also in two unaffected male relatives of the patients. Several possible explanations of this finding are discussed; the most likely being that Val768Ile is a rare non-pathogenic variant. If this were indeed the case, our data suggest that the XHC in this family is not due to a mutation of the L1CAM gene, i.e., that, in addition to the extreme allelic heterogeneity of XHC, a non-allelic form of genetic heterogeneity may also exist in this trait.

    American journal of medical genetics 1997;71;3;336-40

  • Genomic organization of two novel genes on human Xq28: compact head to head arrangement of IDH gamma and TRAP delta is conserved in rat and mouse.

    Brenner V, Nyakatura G, Rosenthal A and Platzer M

    Institut für Molekulare Biotechnologie, Jena, Germany.

    In this paper we present the entire genomic sequence as well as the cDNA sequence of two new human genes encoding the gamma subunit of the NAD(+)-dependent isocitrate dehydrogenase (H-IDH gamma) and the translocon-associated protein delta subunit (TRAP delta). These genes are located on region q28 of the human X chromosome, approximately 70 kb telomeric to the adrenoleukodystrophy locus (ALD). The sequences of the transcripts of both genes were obtained by searching the EST database with genomic data. Identified ESTs were completely sequenced and assembled to cDNAs comprising the entire coding region. For IDH gamma, several EST clones indicate differential splicing. IDH gamma and TRAP delta are arranged in a compact head to head manner. The nontranscribed intergenic region represents only 133 bp and is embedded in a CpG island. The CpG island obviously functions as a bidirectional promoter to initiate the transcription of both functionally unrelated genes with quite distinct expression patterns. This exceptional gene arrangement prompted us to clone and sequence genomic DNA fragments containing the homologous intergenic regions of rat and mouse. We show that in both species this area is similarly compact and represents less than 249 bp in rat and not more than 164 bp in mouse. In both cases this intergenic region is embedded in a CpG island and is highly conserved with nucleotide identity values ranging from 70.1% between human and rat to 92.6% between mouse and rat.

    Genomics 1997;44;1;8-14

  • L1-associated diseases: clinical geneticists divide, molecular geneticists unite.

    Fransen E, Van Camp G, Vits L and Willems PJ

    Department of Medical Genetics, University of Antwerp, Belgium.

    The neuronal cell adhesion molecule L1 (L1CAM) is a transmembrane glycoprotein belonging to the immunoglobulin superfamily and is essential in the development of the nervous system. It is mainly expressed on neurons and Schwann cells, and plays a key role in axon outgrowth and pathfinding through interactions with various extracellular ligands and intracellular second messenger systems. Mutations in L1 are responsible for a wide spectrum of neurologic abnormalities and mental retardation. This spectrum includes X-linked hydrocephalus, MASA syndrome, X-linked complicated spastic paraplegia type 1 and X-linked agenesis of the corpus callosum. These four diseases were initially described as distinct clinical entities with an overlapping clinical spectrum, but can now be lumped into one syndrome caused by mutations in the L1 gene. The main clinical features of this spectrum are Corpus callosum hypoplasia, mental Retardation, Adducted thumbs, Spastic paraplegia and Hydrocephalus, which has led to the acronym CRASH syndrome.

    Human molecular genetics 1997;6;10;1625-32

  • Nine novel L1 CAM mutations in families with X-linked hydrocephalus.

    MacFarlane JR, Du JS, Pepys ME, Ramsden S, Donnai D, Charlton R, Garrett C, Tolmie J, Yates JR, Berry C, Goudie D, Moncla A, Lunt P, Hodgson S, Jouet M and Kenwrick S

    University of Cambridge Department of Medicine, Addenbrooke's Hospital, Cambridge, UK.

    Mutations in the gene for neural cell adhesion molecule L1 are responsible for the highly variable phenotype found in families with X-linked hydrocephalus, MASA syndrome, and spastic paraplegia type I. To date, 32 different mutations have been observed, the majority being unique to individual families. Here, we report nine novel mutations in L1 in 10 X-linked hydrocephalus families. Four mutations truncate the L1 protein and eliminate cell surface expression, and two would produce abnormal L1 through alteration of RNA processing. A further two of these mutations are small in-frame deletions that have occurred through a mechanism involving tandem repeated sequences. Together with a single missense mutation, these latter examples contribute to the growing number of existing mutations that affect short regions of the L1 protein that may have particular functional significance.

    Human mutation 1997;9;6;512-8

  • A new mutation of the L1CAM gene in an X-linked hydrocephalus family.

    Izumoto S, Yamasaki M, Arita N, Hiraga S, Ohnishi T, Fujitani K, Sakoda S and Hayakawa T

    Department of Neurosurgery, Osaka University Medical School, Suita, Japan.

    X-linked hydrocephalus is a genetic form of hydrocephalus that frequently occurs in females. It is characterized by ventricular dilatation, mental retardation, deformity of the thumb and spastic paraparesis. Recently, 23 different mutations of the gene for the neural cell adhesion molecule, L1CAM, located at chromosome region Xq28, have been reported, 16 of which were detected in families with X-linked hydrocephalus. We sequenced the coding region of the L1CAM gene of patients from two different families with X-linked hydrocephalus and found a novel mutation at nucleotide residue 1963 in one family. This mutation from adenine to guanine results in an amino acid change from lysine to glutamic acid at residue 655 of the L1CAM protein, which belongs to the fibronectin type III domain. We report another method of the rapid identification of the mutation based on the polymerase chain reaction. This mutation was not detected among 70 X chromosomes from a healthy population. Ours is the first report demonstrating this gene mutation in X-linked hydrocephalus in an Asian population. Our findings further emphasize the evolving genotypic heterogeneity in X-linked hydrocephalus.

    Child's nervous system : ChNS : official journal of the International Society for Pediatric Neurosurgery 1996;12;12;742-7

  • Outline structure of the human L1 cell adhesion molecule and the sites where mutations cause neurological disorders.

    Bateman A, Jouet M, MacFarlane J, Du JS, Kenwrick S and Chothia C

    MRC Laboratory of Molecular Biology, Cambridge, UK.

    The L1 cell adhesion molecule has six domains homologous to members of the immunoglobulin superfamily and five homologous to fibronectin type III domains. We determined the outline structure of the L1 domains by showing that they have, at the key sites that determine conformation, residues similar to those in proteins of known structure. The outline structure describes the relative positions of residues, the major secondary structures and residue solvent accessibility. We use the outline structure to investigate the likely effects of 22 mutations that cause neurological diseases. The mutations are not randomly distributed but cluster in a few regions of the structure. They can be divided into those that act mainly by changing conformation or denaturing their domain and those that alter its surface properties.

    Funded by: Wellcome Trust

    The EMBO journal 1996;15;22;6050-9

  • L1 adhesion molecule on human lymphocytes and monocytes: expression and involvement in binding to alpha v beta 3 integrin.

    Ebeling O, Duczmal A, Aigner S, Geiger C, Schöllhammer S, Kemshead JT, Möller P, Schwartz-Albiez R and Altevogt P

    Tumor Immunology Programme, German Cancer Research Center, Heidelberg, Germany.

    The L1 adhesion molecule is a member of the immunoglobulin (Ig) superfamily initially identified in the nervous system which contains six Ig-like domains. Besides the known L1-L1 homotypic interaction, L1 was recently shown to bind to very late antigen (VLA)-5 in the mouse and alpha v beta 3 in the human. The sixth Ig domain is critical for this function. We now demonstrate that human CD4+ peripheral blood T lymphocytes, monocytes and B lymphocytes, but not CD8+ T lymphocytes, express L1. When compared to the expression of CD31, another ligand for alpha v beta 3 on T lymphocytes, only a small proportion of cells were CD31+L1+ double positive. L1 was also detected on the surface of human monocytic and lymphoid tumor lines and was shown to have a molecular mass of approximately 220 kDa, similar to the molecule present on neuroblastoma cells. The function of the sixth Ig domain of human L1 as an integrin ligand was also investigated. Using an RGD-containing peptide derived from the sixth Ig domain as well as a fusion protein of the sixth Ig domain of L1 and the Fc portion of human IgG1 (6.L1-Fc), we demonstrated the binding of human MED-B1 (alpha v beta 3hi, alpha 5 beta 1lo) tumor cells and this binding was blocked by alpha v-specific mAb. In contrast, human Nalm-6 cells (alpha v beta 3lo, alpha 5 beta 1hi) did not bind to the 6.L1-Fc fusion protein. MED-B1 cells could also be stained with the 6.L1-Fc fusion protein. Our results suggest that human L1 binds predominantly to alpha v beta 3 and that its presence on leukocytes could be important for adhesion and migration.

    European journal of immunology 1996;26;10;2508-16

  • Involvement of p90rsk in neurite outgrowth mediated by the cell adhesion molecule L1.

    Wong EV, Schaefer AW, Landreth G and Lemmon V

    Department of Neurosciences, Case Western Reserve University, Cleveland, Ohio 44106-4975, USA.

    L1 is a neural cell adhesion molecule that has been shown to help guide nascent axons to their targets. This guidance is based on specific interactions of L1 with its binding partners and is likely to involve signaling cascades that alter cytoskeletal elements in response to these binding events. We have examined the phosphorylation of L1 and the role it may have in L1-directed neurite outgrowth. Cytosolic extracts from nerve growth factor-stimulated PC12 cells were fractionated by anion-exchange chromatography, and an activity was found that phosphorylated the cytoplasmic domain of L1. This activity was then assayed using a battery of L1-derived synthetic peptides. Based on these peptide assays and sequencing of radiolabeled L1 proteolytic fragments, the phosphorylation site was determined to be Ser1152. Western blot analysis demonstrated that the L1 kinase activity from PC12 cells that phosphorylated this site was co-eluted with the S6 kinase, p90(rsk). Moreover, S6 kinase activity and p90(rsk) immunoreactivity co-immunoprecipitate with L1 from brain, and metabolic labeling studies have demonstrated that Ser1152 is phosphorylated in vivo in the developing rat brain. The phosphorylation site is located in a region of high conservation between mammalian L1 sequences as well as L1-related molecules in vertebrates from fish to birds. We performed studies to investigate the functional significance of this phosphorylation. Neurons were loaded with peptides that encompass the phosphorylation site, as well as the flanking regions, and their effects on neurite outgrowth were observed. The peptides, which include Ser1152, inhibit neurite outgrowth on L1 but not on a control substrate, laminin. A nonphosphorylatable peptide carrying a Ser to Ala mutation did not affect neurite outgrowth on either substrate. These data demonstrate that the membrane-proximal 15 amino acids of the cytoplasmic domain of L1 are important for neurite outgrowth on L1, and the interactions it mediates may be regulated by phosphorylation of Ser1152.

    Funded by: NEI NIH HHS: R01 EY005285; PHS HHS: 31987, 5285

    The Journal of biological chemistry 1996;271;30;18217-23

  • Casein kinase II phosphorylates the neural cell adhesion molecule L1.

    Wong EV, Schaefer AW, Landreth G and Lemmon V

    Department of Neurosciences, Case Western Reserve University, Cleveland, OH 44106-4975, USA.

    L1 is an axonal cell adhesion molecule found primarily on projection axons of both the CNS and PNS. It is a phosphorylated membrane-spanning glycoprotein that can be immunoprecipitated from rat brain membranes in association with protein kinase activities. Western blot analysis demonstrates that casein kinase II (CKII), a ubiquitous serine/threonine kinase enriched in brain, is present in these immunoprecipitates. CKII preparations partially purified from PC12 cells are able to phosphorylate recombinant L1 cytoplasmic domain (L1CD), which consists of residues 1,144-1,257. Using these as well as more highly purified kinase preparations, phosphorylation assays of small peptides derived from the L1CD were performed. CKII was able to phosphorylate a peptide encompassing amino acids (aa) 1,173-1,185, as well as a related peptide representing an alternatively spliced nonneuronal L1 isoform that lacks aa 1,177-1,180. Both peptides were phosphorylated with similar kinetic profiles. Serine to alanine substitutions in these peptides indicate that the CKII phosphorylation site is at Ser1,181. This is consistent with experiments in which L1CD was phosphorylated by these kinase preparations, digested, and the radiolabeled fragments sequenced. Furthermore, when L1 immunoprecipitates were used to phosphorylate L1CD, one of the residues phosphorylated is the same residue phosphorylated by CKII. Finally, in vivo radiolabeling indicates that Ser1,181 is phosphorylated in newborn rat brain. These data show that CKII is associated with and able to phosphorylate L1. This phosphorylation may be important in regulating certain aspects of L1 function, such as adhesivity or signal transduction.

    Funded by: NEI NIH HHS: R01 EY005285; NINDS NIH HHS: NS31987; PHS HHS: 5285

    Journal of neurochemistry 1996;66;2;779-86

  • Five novel mutations in the L1CAM gene in families with X linked hydrocephalus.

    Gu SM, Orth U, Veske A, Enders H, Klunder K, Schlosser M, Engel W, Schwinger E and Gal A

    Institut fur Humangenetik, Medizinische Universitat zu Lubeck, Germany.

    Five novel mutations have been identified in the gene encoding L1CAM, a neural cell adhesion protein, in families with X linked hydrocephalus (XHC). Interestingly, all five mutations are in the evolutionarily highly conserved Ig-like domains of the protein. The two frameshift mutations (52insC and 955delG) and the nonsense mutation (Trp276Ter) most probably result in functional null alleles and complete absence of L1CAM at the cell surface. The two missense mutations (Tyr194Cys and Pro240Leu) may considerably alter the structure of the L1CAM protein. These data provide convincing evidence that XHC is genetically extremely heterogeneous.

    Journal of medical genetics 1996;33;2;103-6

  • A locus-specific mutation database for the neural cell adhesion molecule L1CAM (Xq28)

    Van Camp G, Fransen E, Vits L, Raes G and Willems PJ

    Human mutation 1996;8;4;391

  • The F3 neuronal glycosylphosphatidylinositol-linked molecule is localized to glycolipid-enriched membrane subdomains and interacts with L1 and fyn kinase in cerebellum.

    Olive S, Dubois C, Schachner M and Rougon G

    Laboratoire de Génétique et Physiologie du Développement, UMR 9943 CNRS-Université Aix-Marseille II, Paris, France.

    The F3 molecule is a member of the immunoglobulin superfamily anchored to plasma membranes by a glycosylphosphatidylinositol group. In adult mouse cerebellum, F3 is predominantly expressed on a subset of axons, the parallel fibers, and at their synapses. In vitro studies established that it is a plurifunctional molecule that, depending on the cellular context and the ligand with which it interacts, either mediates repulsive interactions or promotes neurite outgrowth. In the present study, we report the isolation of two fractions of F3-containing microdomains from adult cerebellum on the basis of their resistance to solubilization by Triton X-100 at 4 degrees C. Both fractions were composed of vesicles, ranging from 100 to 200 nm in diameter. Lipid composition analysis indicated that the lighter fraction was enriched in cerebrosides and sulfatides. F3 sensitivity to phosphatidylinositol phospholipase C differed between the two fractions, possibly reflecting structural differences in the lipid anchor of the F3 molecule. Both fractions were highly enriched in other glycosylphosphatidylinositol-anchored proteins such as NCAM 120 and Thy-1. It is interesting that these vesicles were devoid of the transmembrane forms (NCAM 180 and NCAM 140), which were recovered in Triton X-100-soluble fractions, but contained the L1 transmembrane adhesion molecule that is coexpressed with F3 on parallel fibers and the fyn tyrosine kinase. Immunoprecipitation experiments indicated that F3, but not NCAM 120 or Thy-1, was physically associated in a complex with both L1 and fyn tyrosine kinase. This strongly suggests that the interaction between L1 and F3, already described to occur with isolated molecules, is present in neural tissue. More important is that our study provides information on the molecular machinery likely to be involved in F3 signaling.

    Journal of neurochemistry 1995;65;5;2307-17

  • Mutations in L1-CAM in two families with X linked complicated spastic paraplegia, MASA syndrome, and HSAS.

    Ruiz JC, Cuppens H, Legius E, Fryns JP, Glover T, Marynen P and Cassiman JJ

    Centre for Human Genetics, University of Leuven, Belgium.

    The suggestion that the three X linked syndromes X linked spastic paraplegia (MIM 312900), MASA syndrome (MIM 303350), and X linked hydrocephalus owing to stenosis of the aqueduct of Sylvius (MIM 307000) are variable clinical manifestations of mutations at the same locus at Xq28 was confirmed by the finding of mutations in the L1-CAM gene in the three syndromes. Recently, two families in which different subjects showed a clearly different phenotype within the same family of the three X linked syndromes were described. A reverse transcription PCR assay was developed for the analysis of the L1-CAM cDNA in two of the members of these families. RNA isolated from EBV transformed cell lines and a colon carcinoma derived cell line was used as a starting material. The L1-CAM cDNA of two male patients from each family was sequenced. We report two new mutations in the L1-CAM gene in these two families showing that the three different phenotypes observed in different generations within the same family are variable phenotypic expressions of the same mutation.

    Journal of medical genetics 1995;32;7;549-52

  • New domains of neural cell-adhesion molecule L1 implicated in X-linked hydrocephalus and MASA syndrome.

    Jouet M, Moncla A, Paterson J, McKeown C, Fryer A, Carpenter N, Holmberg E, Wadelius C and Kenwrick S

    University of Cambridge Department of Medicine, Addenbrooke's Hospital, United Kingdom.

    The neural cell-adhesion molecule L1 is involved in intercellular recognition and neuronal migration in the CNS. Recently, we have shown that mutations in the gene encoding L1 are responsible for three related disorders; X-linked hydrocephalus, MASA (mental retardation, aphasia, shuffling gait, and adducted thumbs) syndrome, and spastic paraplegia type I (SPG1). These three disorders represent a clinical spectrum that varies not only between families but sometimes also within families. To date, 14 independent L1 mutations have been reported and shown to be disease causing. Here we report nine novel L1 mutations in X-linked hydrocephalus and MASA-syndrome families, including the first examples of mutations affecting the fibronectin type III domains of the molecule. They are discussed in relation both to phenotypes and to the insights that they provide into L1 function.

    American journal of human genetics 1995;56;6;1304-14

  • CRASH syndrome: clinical spectrum of corpus callosum hypoplasia, retardation, adducted thumbs, spastic paraparesis and hydrocephalus due to mutations in one single gene, L1.

    Fransen E, Lemmon V, Van Camp G, Vits L, Coucke P and Willems PJ

    Department of Medical Genetics, University of Antwerp, Belgium.

    L1 is a neuronal cell adhesion molecule with important functions in the development of the nervous system. The gene encoding L1 is located near the telomere of the long arm of the X chromosome in Xq28. We review here the evidence that several X-linked mental retardation syndromes including X-linked hydrocephalus (HSAS), MASA syndrome, X-linked complicated spastic paraparesis (SP1) and X-linked corpus callosum agenesis (ACC) are all due to mutations in the L1 gene. The inter- and intrafamilial variability in families with an L1 mutation is very wide, and patients with HSAS, MASA, SP1 and ACC can be present within the same family. Therefore, we propose here to refer to this clinical syndrome with the acronym CRASH, for Corpus callosum hypoplasia, Retardation, Adducted thumbs, Spastic paraplegia and Hydrocephalus.

    Funded by: NEI NIH HHS: R01 EY005285

    European journal of human genetics : EJHG 1995;3;5;273-84

  • X-linked hydrocephalus and MASA syndrome present in one family are due to a single missense mutation in exon 28 of the L1CAM gene.

    Fransen E, Schrander-Stumpel C, Vits L, Coucke P, Van Camp G and Willems PJ

    Department of Medical Genetics, University of Antwerp-UIA, Belgium.

    Human molecular genetics 1994;3;12;2255-6

  • MASA syndrome is due to mutations in the neural cell adhesion gene L1CAM.

    Vits L, Van Camp G, Coucke P, Fransen E, De Boulle K, Reyniers E, Korn B, Poustka A, Wilson G, Schrander-Stumpel C et al.

    Department of Medical Genetics, University of Antwerp, Belgium.

    MASA syndrome is a recessive X-linked disorder characterized by mental retardation, adducted thumbs, shuffling gait, aphasia and, in some cases, hydrocephalus. Since it has been shown that X-linked hydrocephalus can be caused by mutations in L1CAM, a neuronal cell adhesion molecule, we performed an L1CAM mutation analysis in eight unrelated patients with MASA syndrome. Three different L1CAM mutations were identified: a deletion removing part of the open reading frame and two point mutations resulting in amino acid substitutions. L1CAM, therefore, harbours mutations leading to either MASA syndrome or HSAS, and might be frequently implicated in X-linked mental retardation with or without hydrocephalus.

    Nature genetics 1994;7;3;408-13

  • X-linked spastic paraplegia (SPG1), MASA syndrome and X-linked hydrocephalus result from mutations in the L1 gene.

    Jouet M, Rosenthal A, Armstrong G, MacFarlane J, Stevenson R, Paterson J, Metzenberg A, Ionasescu V, Temple K and Kenwrick S

    Department of Medicine, University of Cambridge, Addenbrooke's Hospital, UK.

    X-linked hydrocephalus, spastic paraplegia type I and MASA syndrome are related disorders with loci in subchromosomal region Xq28. We have previously shown that X-linked hydrocephalus is caused by mutations in the gene for neural cell adhesion molecule L1 (L1CAM), an axonal glycoprotein involved in neuronal migration and differentiation. Here we report mutations of the L1 gene in MASA syndrome and SPG1, in addition to HSAS families. Two of the HSAS mutations would abolish cell surface expression of L1 and represent the first functional null mutations in this disorder. Our results indicate that these three syndromes from part of a clinical spectrum resulting from a heterogeneous group of mutations in the L1 gene.

    Nature genetics 1994;7;3;402-7

  • The neuronal chondroitin sulfate proteoglycan neurocan binds to the neural cell adhesion molecules Ng-CAM/L1/NILE and N-CAM, and inhibits neuronal adhesion and neurite outgrowth.

    Friedlander DR, Milev P, Karthikeyan L, Margolis RK, Margolis RU and Grumet M

    Department of Pharmacology, New York University Medical Center, New York 10016.

    We have previously shown that aggregation of microbeads coated with N-CAM and Ng-CAM is inhibited by incubation with soluble neurocan, a chondroitin sulfate proteoglycan of brain, suggesting that neurocan binds to these cell adhesion molecules (Grumet, M., A. Flaccus, and R. U. Margolis. 1993. J. Cell Biol. 120:815). To investigate these interactions more directly, we have tested binding of soluble 125I-neurocan to microwells coated with different glycoproteins. Neurocan bound at high levels to Ng-CAM and N-CAM, but little or no binding was detected to myelin-associated glycoprotein, EGF receptor, fibronectin, laminin, and collagen IV. The binding to Ng-CAM and N-CAM was saturable and in each case Scatchard plots indicated a high affinity binding site with a dissociation constant of approximately 1 nM. Binding was significantly reduced after treatment of neurocan with chondroitinase, and free chondroitin sulfate inhibited binding of neurocan to Ng-CAM and N-CAM. These results indicate a role for chondroitin sulfate in this process, although the core glycoprotein also has binding activity. The COOH-terminal half of neurocan was shown to have binding properties essentially identical to those of the full-length proteoglycan. To study the potential biological functions of neurocan, its effects on neuronal adhesion and neurite growth were analyzed. When neurons were incubated on dishes coated with different combinations of neurocan and Ng-CAM, neuronal adhesion and neurite extension were inhibited. Experiments using anti-Ng-CAM antibodies as a substrate also indicate that neurocan has a direct inhibitory effect on neuronal adhesion and neurite growth. Immunoperoxidase staining of tissue sections showed that neurocan, Ng-CAM, and N-CAM are all present at highest concentration in the molecular layer and fiber tracts of developing cerebellum. The overlapping localization in vivo, the molecular binding studies, and the striking effects on neuronal adhesion and neurite growth support the view that neurocan may modulate neuronal adhesion and neurite growth during development by binding to neural cell adhesion molecules.

    Funded by: NINDS NIH HHS: NS-09348, NS-13876, NS-21629

    The Journal of cell biology 1994;125;3;669-80

  • A missense mutation confirms the L1 defect in X-linked hydrocephalus (HSAS)

    Jouet M, Rosenthal A, MacFarlane J, Kenwrick S and Donnai D

    Nature genetics 1993;4;4;331

  • The fourth immunoglobulin-like domain of NCAM contains a carbohydrate recognition domain for oligomannosidic glycans implicated in association with L1 and neurite outgrowth.

    Horstkorte R, Schachner M, Magyar JP, Vorherr T and Schmitz B

    Department of Neurobiology, Swiss Federal Institute of Technology, Zürich.

    We have previously shown that the neural adhesion molecules L1 and NCAM interact with each other to form a complex which binds more avidly to L1 than L1 to L1 alone (Kadmon, G., A. Kowitz, P. Altevogt, and M. Schachner. 1990a. J. Cell Biol. 110:193-208). This cis-association between L1 and NCAM is carbohydrate-dependent (Kadmon, G., A. Kowitz, P. Altevogt, and M. Schachner. 1990b. J. Cell Biol. 110:209-218). In the present study, we report that L1 and NCAM bind to each other via oligomannosidic carbohydrates expressed by L1, but not by NCAM, as shown in several experiments: (a) complex formation between L1 and NCAM is inhibited by a mAb to oligomannosidic carbohydrates and by the oligosaccharides themselves; (b) NCAM binds to oligomannosidic carbohydrates; (c) within the L1/NCAM complex, the oligomannosidic carbohydrates are hidden from accessibility to a mAb against oligomannosidic carbohydrates; (d) the recombinant protein fragment of NCAM containing the immunoglobulin-like domains and not the fragment containing the fibronectin type III homologous repeats binds to oligomannosidic glycans. Furthermore, the fourth immunoglobulin-like domain of NCAM shows sequence homology with carbohydrate recognition domains of animal C-type lectins and, surprisingly, also with plant lectins. A peptide comprising part of the C-type lectin consensus sequence in the fourth immunoglobulin-like domain of NCAM interferes with the association between L1 and NCAM. The functional importance of oligomannosidic glycans at the cell surface was shown for neurite outgrowth in vitro. When neurons from early postnatal mouse cerebellum were maintained on laminin or poly-L-lysine, neurite outgrowth was inhibited by oligomannosidic glycans, by glycopeptides, glycoproteins, or neoglycolipids containing oligomannosidic glycans, but not by nonrelated oligosaccharides or oligosaccharide derivates. Neurite outgrowth was also inhibited by the peptide comprising part of the C-type lectin consensus sequence in the fourth immunoglobulin-like domain of NCAM. The combined results suggest that carbohydrate-mediated cis-associations between adhesion molecules at the cell surface modulate their functional properties.

    The Journal of cell biology 1993;121;6;1409-21

  • Aberrant splicing of neural cell adhesion molecule L1 mRNA in a family with X-linked hydrocephalus.

    Rosenthal A, Jouet M and Kenwrick S

    Department of Medicine, University of Cambridge, Addenbrooke's Hospital, UK.

    A locus for X-linked hydrocephalus (HSAS), which is characterized by mental retardation and enlarged brain ventricles, maps to the same subchromosomal region (Xq28) as the gene for neural cell adhesion molecule L1. We have found novel L1 mRNA species in cells from affected members of a HSAS family containing deletions and insertions produced by the utilization of alternative 3' splice sites. A point mutation at a potential branch point signal in an intron segregates with the disease and is likely to be responsible for the abnormal RNA processing. These results suggest that HSAS is a disorder of neuronal cell migration due to disruption of L1 protein function.

    Nature genetics 1992;2;2;107-12

  • Variants of human L1 cell adhesion molecule arise through alternate splicing of RNA.

    Reid RA and Hemperly JJ

    Becton Dickinson and Company Research Center, Research Triangle Park, NC 27709-2016.

    The L1 cell adhesion molecule was initially identified and characterized in mouse as a cell-surface glycoprotein that mediates neuron-neuron and neuron-Schwann cell adhesion. We have characterized L1 in humans using cDNA structural and mRNA expression analyses. We present the entire coding sequence for human L1, which predicts a 1253-amino acid protein displaying a signal sequence, transmembrane segment, RGD sequence, and potential glycosylation and phosphorylation sites. Nucleotide and deduced amino acid sequence identities between human and mouse L1 are 85% and 87%, respectively. In contrast, the amino acid identity between human L1 and the L1-related molecule chicken Ng-CAM is only 45%. Using Northern blot analyses, a single L1 transcript of 5.5 kb is detected in human fetal brain and in neuroblastoma (IMR-32) and retinoblastoma (Y-79) cell lines. L1 is also expressed in the rhabdomyosarcoma cell lines RD and A-204, which display several muscle characteristics. Two forms of L1, which differ by the presence or absence of a 12-bp cytoplasmic segment, are expressed in both human and mouse. This segment is encoded by a single exon that can be alternately spliced to give rise to the two forms, which appear to be expressed in tissue-specific patterns.

    Journal of molecular neuroscience : MN 1992;3;3;127-35

  • PCR walking from microdissection clone M54 identifies three exons from the human gene for the neural cell adhesion molecule L1 (CAM-L1).

    Rosenthal A, MacKinnon RN and Jones DS

    MRC Molecular Genetics Unit, Cambridge, UK.

    Microdissection has proved to be a powerful tool in the construction of libraries from specific chromosome segments (11) which are poorly covered by existing RFLP markers. Microclones also represent starting points for finding genes of interest. However, their length (100 to 200 bp) can make their use as probes problematic and identifying them as coding sequence is difficult. We report here that microclones can be extended in vitro by a modified version of our original PCR walking method (10) which utilises oligo-cassettes and the solid phase biotin/streptavidin separation system. We have extended the microclone M54, derived by dissection from Xq27.2 to proximal Xq28 (12), in both directions for approximately 700 bp. Direct sequencing of these products revealed that M54 was located within an intron of the human gene encoding the neural cell adhesion molecule L1 (CAM-L1) which has been recently mapped to Xq28 (13). The extension of M54 also identified three exons of this gene. This information allowed subsequent amplification of a 2.4 kb cDNA molecule from fetal human brain mRNA which encodes most of human CAM-L1. Sequencing of this cDNA revealed a high degree of sequence conservation with the mouse homologue (14). This is the first description of extension of a human derived microclone by PCR mediated walking within total human genomic DNA. These results show that anonymous DNA sequences may be extended into coding or any sequence.

    Nucleic acids research 1991;19;19;5395-401

  • Molecular cloning of cell adhesion molecule L1 from human nervous tissue: a comparison of the primary sequences of L1 molecules of different origin.

    Kobayashi M, Miura M, Asou H and Uyemura K

    Department of Physiology, Keio University School of Medicine, Tokyo, Japan.

    Complementary DNA for the human neural cell adhesion molecule L1 was cloned and sequenced: the deduced amino acid sequence consists of 1257 amino acid residues containing six repeats of the immunoglobulin C2 domain and five repeats of the fibronectin type III domain. The intracellular domain of human L1 is highly conserved as compared to mouse, but not identical to L1 cloned from human melanoma cells, suggesting the existence of alternative forms in the same species.

    Biochimica et biophysica acta 1991;1090;2;238-40

  • Molecular structure and functional testing of human L1CAM: an interspecies comparison.

    Hlavin ML and Lemmon V

    Department of Neurosurgery, Case Western Reserve University, Cleveland, Ohio 44106.

    The rodent, avian, and insect L1-like cell adhesion molecules are members of the immunoglobulin superfamily that have been implicated in axon growth. We have isolated an L1-like molecule from human brain and found that it also supports neurite growth in vitro. We have also cloned and sequenced the entire coding region of human L1CAM and found that it shows a very high degree of homology to mouse L1cam, with 92% identity at the amino acid level. This similarity suggests that L1CAM is an important molecule in normal human nervous system development and nerve regeneration. Overall, there is substantially less homology to chick Ng-CAM; they are 40% identical at the amino acid level but many regions are highly conserved. Comparison of the sequences from human, mouse, chick, and Drosophila indicates that the L1 immunoglobulin domain 2 and fibronectin type III domain 2 are strongly conserved and thus are likely functionally important.

    Funded by: NEI NIH HHS: R01 EY005285; PHS HHS: 5285

    Genomics 1991;11;2;416-23

  • X linked complicated spastic paraplegia, MASA syndrome, and X linked hydrocephalus owing to congenital stenosis of the aqueduct of Sylvius: variable expression of the same mutation at Xq28.

    Fryns JP, Spaepen A, Cassiman JJ and van den Berghe H

    Journal of medical genetics 1991;28;6;429-31

  • Isolation and sequence of partial cDNA clones of human L1: homology of human and rodent L1 in the cytoplasmic region.

    Harper JR, Prince JT, Healy PA, Stuart JK, Nauman SJ and Stallcup WB

    La Jolla Cancer Research Foundation, California.

    We have isolated cDNA clones coding for the human homologue of the neuronal cell adhesion molecule L1. The nucleotide sequence of the cDNA clones and the deduced primary amino acid sequence of the carboxy terminal portion of the human L1 are homologous to the corresponding sequences of mouse L1 and rat NILE glycoprotein, with an especially high sequences identity in the cytoplasmic regions of the proteins. There is also protein sequence homology with the cytoplasmic region of the Drosophila cell adhesion molecule, neuroglian. The conservation of the cytoplasmic domain argues for an important functional role for this portion of the molecule.

    Funded by: NCI NIH HHS: R29 CA 45626; NICHD NIH HHS: P01 HD 25938; NINDS NIH HHS: R01 NS 23126

    Journal of neurochemistry 1991;56;3;797-804

  • The gene encoding L1, a neural adhesion molecule of the immunoglobulin family, is located on the X chromosome in mouse and man.

    Djabali M, Mattei MG, Nguyen C, Roux D, Demengeot J, Denizot F, Moos M, Schachner M, Goridis C and Jordan BR

    CIML INSERM-CNRS, Marseille, France.

    The murine and human genes for the L1 neural adhesion molecule were shown to lie on conserved regions of the X chromosome to which genes responsible for several neuromuscular diseases have been mapped and which are adjacent to the fragile site (FRAXA) associated with mental retardation. By pulsed-field gel mapping we have demonstrated physical linkage between the L1 gene and other genes located in Xq28: L1 lies between the eye pigment RCP, GCP locus and the glucose-6-phosphate dehydrogenase (G6PD) gene. This location is compatible with the implication of the L1 molecule in one of the X-linked neuromuscular diseases mapped to this region.

    Genomics 1990;7;4;587-93

  • A human brain glycoprotein related to the mouse cell adhesion molecule L1.

    Wolff JM, Frank R, Mujoo K, Spiro RC, Reisfeld RA and Rathjen FG

    Max-Planck-Institut für Entwicklungsbiologie, Tübingen, Federal Republic of Germany.

    We have employed monoclonal antibody 5G3, an antibody used to label human tumor cells of neural origin (Mujoo, K., Spiro, R.C., and Reisfeld, R. A. (1986) J. Biol. Chem. 261, 10299-10305), to isolate and characterize a large glycoprotein from normal adult human brain. This protein was compared to mouse L1 (Rathjen, F. G., and Schachner, M. (1984) EMBO J. 3, 1-10), a neural cell surface glycoprotein implicated predominantly in neurite-neurite interactions. On the basis of the following results the 5G3 antigen is considered to be the human homologue of mouse L1. In sodium dodecyl sulfate-polyacrylamide gel electrophoresis, both proteins share similar molecular masses of their carbohydrate-depleted or undepleted components. In tryptic fingerprint analyses of the iodinated L1 and 5G3 components, 65% of the resolved peptides comigrated. Comparison of NH2-terminal amino acid sequences revealed a high degree of homology between human 5G3 and mouse L1, with 11 of 15 residues being identical. Furthermore, polyclonal antibodies to human 5G3 antigen were found to be cross-reactive with mouse L1 antigen and vice versa. All components of 5G3 and L1 antigens show considerable charge heterogeneity with partial overlapping of regions in isoelectric focusing followed by sodium dodecyl sulfate polyacrylamide gel electrophoresis. These findings provide a basis for studying the role of the human L1 homologue in human diseases.

    The Journal of biological chemistry 1988;263;24;11943-7

Gene lists (8)

Gene List Source Species Name Description Gene count
L00000009 G2C Homo sapiens Human PSD Human orthologues of mouse PSD adapted from Collins et al (2006) 1080
L00000013 G2C Homo sapiens Human mGluR5 Human orthologues of mouse mGluR5 complex adapted from Collins et al (2006) 52
L00000015 G2C Homo sapiens Human NRC Human orthologues of mouse NRC adapted from Collins et al (2006) 186
L00000016 G2C Homo sapiens Human PSP Human orthologues of mouse PSP adapted from Collins et al (2006) 1121
L00000059 G2C Homo sapiens BAYES-COLLINS-HUMAN-PSD-CONSENSUS Human cortex PSD consensus 748
L00000061 G2C Homo sapiens BAYES-COLLINS-MOUSE-PSD-CONSENSUS Mouse cortex PSD consensus (ortho) 984
L00000069 G2C Homo sapiens BAYES-COLLINS-HUMAN-PSD-FULL Human cortex biopsy PSD full list 1461
L00000071 G2C Homo sapiens BAYES-COLLINS-MOUSE-PSD-FULL Mouse cortex PSD full list (ortho) 1556
© G2C 2014. The Genes to Cognition Programme received funding from The Wellcome Trust and the EU FP7 Framework Programmes:
EUROSPIN (FP7-HEALTH-241498), SynSys (FP7-HEALTH-242167) and GENCODYS (FP7-HEALTH-241995).

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