G2Cdb::Gene report

Gene id
G00001879
Gene symbol
HAPLN1 (HGNC)
Species
Homo sapiens
Description
hyaluronan and proteoglycan link protein 1
Orthologue
G00000630 (Mus musculus)

Databases (7)

Gene
ENSG00000145681 (Ensembl human gene)
1404 (Entrez Gene)
1055 (G2Cdb plasticity & disease)
HAPLN1 (GeneCards)
Literature
115435 (OMIM)
Marker Symbol
HGNC:2380 (HGNC)
Protein Sequence
P10915 (UniProt)

Literature (25)

Pubmed - other

  • Sequential use of transcriptional profiling, expression quantitative trait mapping, and gene association implicates MMP20 in human kidney aging.

    Wheeler HE, Metter EJ, Tanaka T, Absher D, Higgins J, Zahn JM, Wilhelmy J, Davis RW, Singleton A, Myers RM, Ferrucci L and Kim SK

    Department of Genetics, Stanford University Medical Center, Stanford, California, USA.

    Kidneys age at different rates, such that some people show little or no effects of aging whereas others show rapid functional decline. We sequentially used transcriptional profiling and expression quantitative trait loci (eQTL) mapping to narrow down which genes to test for association with kidney aging. We first performed whole-genome transcriptional profiling to find 630 genes that change expression with age in the kidney. Using two methods to detect eQTLs, we found 101 of these age-regulated genes contain expression-associated SNPs. We tested the eQTLs for association with kidney aging, measured by glomerular filtration rate (GFR) using combined data from the Baltimore Longitudinal Study of Aging (BLSA) and the InCHIANTI study. We found a SNP association (rs1711437 in MMP20) with kidney aging (uncorrected p = 3.6 x 10(-5), empirical p = 0.01) that explains 1%-2% of the variance in GFR among individuals. The results of this sequential analysis may provide the first evidence for a gene association with kidney aging in humans.

    Funded by: Intramural NIH HHS; NIA NIH HHS: R01 AG025941, R01 AG025941-01A2; NIMHD NIH HHS: 263 MD 821336, 263 MD 9164, R01 MD009164

    PLoS genetics 2009;5;10;e1000685

  • Glypican 5 is an interferon-beta response gene: a replication study.

    Cénit MD, Blanco-Kelly F, de las Heras V, Bartolomé M, de la Concha EG, Urcelay E, Arroyo R and Martínez A

    Clinical Immunology Department, Hospital Clínico San Carlos, Madrid, Spain.

    Background: Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system. Interferon-beta is the most usual therapy in relapsing-remiting MS. However, approximately 50% of the treated patients do not respond adequately. Very recently, a genome-wide association study on interferon-beta pharmacogenetics has described polymorphisms at several genes that are associated with response to this treatment. Our aim is to replicate the results obtained at the two loci most strongly implicated in the response to interferon-beta treatment, HAPLN1 and GPC5.

    We performed a case-control study, analyzing 199 patients with MS treated with interferon-beta for at least 2 years and at least two documented relapses over the 2 years, previous to treatment onset. Responders had neither relapses nor increase in expanded disability status scale (EDSS) over the 2-year follow-up period, whereas nonresponders had at least two relapses or an increase in EDSS of at least 1 point. We studied three single-nucleotide polymorphisms (SNPs) in the GPC5 locus and three SNPs in the HAPLN1 locus by TaqMan technology. Allelic frequencies between responders and nonresponders were compared by a chi-square test.

    Results: An association was found between GPC5 polymorphisms and the response to interferon-beta therapy in patients with MS, in agreement with earlier data (responder vs nonresponder patients: rs10492503, P = 0.0005). The other locus studied (HAPLN1) did not show association with treatment response to interferon-beta (all SNPs P > 0.05).

    Conclusions: We confirm the association of polymorphisms within GPC5 with response to interferon-beta therapy in patients with MS.

    Multiple sclerosis (Houndmills, Basingstoke, England) 2009;15;8;913-7

  • Protumorigenic role of HAPLN1 and its IgV domain in malignant pleural mesothelioma.

    Ivanova AV, Goparaju CM, Ivanov SV, Nonaka D, Cruz C, Beck A, Lonardo F, Wali A and Pass HI

    Department of Cardiothoracic Surgery, Langone School of Medicine, New York University, New York, New York, USA. alla.ivanova@vanderbilt.edu

    Purpose: Tumor extracellular matrix (ECM) plays a crucial role in cancer progression mediating and transforming host-tumor interactions. Targeting the ECM is becoming an increasingly promising therapeutic approach in cancer treatment. We find that one of the ECM proteins, HAPLN1, is overexpressed in the majority of mesotheliomas. This study was designed to characterize the protumorigenic role of HAPLN1 in mesothelioma.

    Overexpression of HAPLN1 was assessed and validated on a large set of normal/mesothelioma specimens on the RNA and protein levels. We also analyzed DNA copy number alterations in the HAPLN1 genomic locus using the array-based comparative genomic hybridization representational oligonucleotide microarray analysis tool. Tumorigenic activities of the HAPLN1 domains were evaluated in vitro on mesothelioma cells transfected with HAPLN1-expressing constructs.

    Results: We found that HAPLN1 is 23-fold overexpressed in stage I mesothelioma and confirmed it for 76% samples (n = 53) on RNA and 97% (n = 40) on protein levels. The majority of lung cancers showed no differential expression of HAPLN1. Analysis of DNA copy number alterations identified recurrent gain in the 5q14.3 HAPLN1 locus in approximately 27% of tumors. Noteworthy, high expression of HAPLN1 negatively correlated with time to progression (P = 0.05, log-rank test) and overall survival (P = 0.006). Proliferation, motility, invasion, and soft-agar colony formation assays on mesothelioma cells overexpressing full-length HAPLN1 or its functional domains strongly supported the protumorigenic role of HAPLN1 and its SP-IgV domain.

    Conclusion: Overexpression of HAPLN1 and its SP-IgV domain increases tumorigenic properties of mesothelioma. Thus, targeting the SP-IgV domain may be one of the therapeutic approaches in cancer treatment.

    Funded by: NCI NIH HHS: 5 U01 CA111295-02, P01 CA114047, U01 CA111295

    Clinical cancer research : an official journal of the American Association for Cancer Research 2009;15;8;2602-11

  • A genome-wide association study of breast and prostate cancer in the NHLBI's Framingham Heart Study.

    Murabito JM, Rosenberg CL, Finger D, Kreger BE, Levy D, Splansky GL, Antman K and Hwang SJ

    The National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, MA, USA. murabito@bu.edu

    Background: Breast and prostate cancer are two commonly diagnosed cancers in the United States. Prior work suggests that cancer causing genes and cancer susceptibility genes can be identified.

    Methods: We conducted a genome-wide association study (Affymetrix 100K SNP GeneChip) of cancer in the community-based Framingham Heart Study. We report on 2 cancer traits--prostate cancer and breast cancer--in up to 1335 participants from 330 families (54% women, mean entry age 33 years). Multivariable-adjusted residuals, computed using Cox proportional hazards models, were tested for association with qualifying SNPs (70, 987 autosomal SNPs with genotypic call rate > or =80%, minor allele frequency > or =10%, Hardy-Weinberg test p > or = 0.001) using generalized estimating equations (GEE) models and family based association tests (FBAT).

    Results: There were 58 women with breast cancer and 59 men with prostate cancer. No SNP associations attained genome-wide significance. The top SNP associations in GEE models for each trait were as follows: breast cancer, rs2075555, p = 8.0 x 10(-8) in COL1A1; and prostate cancer, rs9311171, p = 1.75 x 10(-6) in CTDSPL. In analysis of selected candidate cancer susceptibility genes, two MSR1 SNPs (rs9325782, GEE p = 0.008 and rs2410373, FBAT p = 0.021) were associated with prostate cancer and three ERBB4 SNPs (rs905883 GEE p = 0.0002, rs7564590 GEE p = 0.003, rs7558615 GEE p = 0.0078) were associated with breast cancer. The previously reported risk SNP for prostate cancer, rs1447295, was not included on the 100K chip. Results of cancer phenotype-genotype associations for all autosomal SNPs are web posted at http://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?id=phs000007 webcite.

    Conclusion: Although no association attained genome-wide significance, several interesting associations emerged for breast and prostate cancer. These findings can serve as a resource for replication in other populations to identify novel biologic pathways contributing to cancer susceptibility.

    Funded by: NCRR NIH HHS: 1S10RR163736-01A1; NHLBI NIH HHS: N01-HC-25195, N01HC25195

    BMC medical genetics 2007;8 Suppl 1;S6

  • Expression and purification of functionally active hyaluronan-binding domains from human cartilage link protein, aggrecan and versican: formation of ternary complexes with defined hyaluronan oligosaccharides.

    Seyfried NT, McVey GF, Almond A, Mahoney DJ, Dudhia J and Day AJ

    Medical Research Council Immunochemistry Unit, Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, UK.

    The chondroitin sulfate proteoglycan aggrecan forms link protein-stabilized complexes with hyaluronan (HA), via its N-terminal G1-domain, that provide cartilage with its load bearing properties. Similar aggregates (potentially containing new members of the link protein family), in which other chondroitin sulfate proteoglycans (i.e. versican, brevican, and neurocan) substitute for aggrecan, may contribute to the structural integrity of many other tissues including skin and brain. In this study, cartilage link protein (cLP) and the G1-domains of aggrecan (AG1) and versican (VG1) were expressed in Drosophila S2 cells. The recombinant human proteins were found to have properties similar to those described for the native molecules (e.g. cLP was able to form oligomers, and HA decasaccharides were the minimum size that could compete effectively for their binding to polymeric HA). Gel filtration and protein cross-linking/matrix-assisted laser desorption ionization time-of-flight peptide fingerprinting showed that cLP and AG1 interact in the absence or presence of HA. Conversely, cLP and VG1 did not bind directly to each other in solution yet formed ternary complexes with HA24. N-linked glycosylation of AG1 and VG1 was demonstrated to be unnecessary for either HA binding or the formation of ternary complexes. Surprisingly, the length of HA required to accommodate two G1-domains was found to be significantly larger for aggrecan than versican, which may reflect differences in the conformation of HA stabilized on binding these proteins.

    Funded by: Medical Research Council: MC_U138274352

    The Journal of biological chemistry 2005;280;7;5435-48

  • SOX9-dependent and -independent transcriptional regulation of human cartilage link protein.

    Kou I and Ikegawa S

    Laboratory for Bone and Joint Diseases, SNP Research Center, RIKEN, Tokyo 108-8639, Japan.

    Cartilage link protein is a key component of the cartilage extracellular matrix. The transcriptional regulation of the gene encoding cartilage link protein (CRTL1) is largely unknown, however. Here, we investigated the regulation of CRTL1 by SOX9, a key regulator of cartilage matrix genes and chondrogenesis. Knockdown of SOX9 resulted in decreased CRTL1 expression. SOX9 induced CRTL1 expression effectively in human non-chondrocytic immortalized cell lines as well as in mesenchymal stem cell and adult dermal fibroblast. These results indicate that, like other cartilage matrix genes, SOX9 is a key regulator of CRTL1. Unlike other cartilage matrix genes, however, the activation of CRTL1 by SOX9 and its known transcriptional co-activators L-SOX5 and SOX6 was cell type-dependent. Two cis-acting enhancer elements resided in the 5'-untranslated region of CRTL1. One contained a heptameric SOX binding sequence and showed SOX9-dependent enhancer activity in several cell lines. The other showed cell type-specific SOX9-independent enhancer activity. These findings suggest that the enhancer elements may mediate differential expression of CRTL1 during chondrocyte differentiation and maturation.

    The Journal of biological chemistry 2004;279;49;50942-8

  • 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

  • Link protein has greater affinity for versican than aggrecan.

    Shi S, Grothe S, Zhang Y, O'Connor-McCourt MD, Poole AR, Roughley PJ and Mort JS

    Joint Diseases Laboratory, Shriners Hospitals for Children, 1529 Cedar Avenue, Montreal, Quebec, Canada H3G 1A6.

    The function of link protein in stabilizing the interaction between aggrecan and hyaluronan to form aggrecan aggregates, via the binding of link protein to the aggrecan G1 domain and hyaluronan, is well established. However, it is not known whether link protein can function with similar avidity with versican, another member of the large hyaluronan-binding proteoglycan family that also binds to hyaluronan via its G1 domain. To address this issue, we have compared the interaction of the versican and aggrecan G1 domains with link protein and hyaluronan using recombinant proteins expressed in insect cells and BIAcore analysis. The results showed that link protein could significantly improve the binding of both G1 domains to hyaluronan and that its interaction with VG1 is of a higher affinity than that with AG1. These observations suggest that link protein may function as a stabilizer of the interaction, not only between aggrecan and hyaluronan in cartilage, but also between versican and hyaluronan in many tissues.

    The Journal of biological chemistry 2004;279;13;12060-6

  • Distinct interaction of versican/PG-M with hyaluronan and link protein.

    Matsumoto K, Shionyu M, Go M, Shimizu K, Shinomura T, Kimata K and Watanabe H

    Institute for Molecular Science of Medicine, Aichi Medical University, Nagakute, Aichi 480-1195.

    The proteoglycan aggregate is the major structural component of the cartilage matrix, comprising hyaluronan (HA), link protein (LP), and a large chondroitin sulfate (CS) proteoglycan, aggrecan. Here, we found that another member of aggrecan family, versican, biochemically binds to both HA and LP. Functional analyses of recombinant looped domains (subdomains) A, B, and B' of the N-terminal G1 domain revealed that the B-B' segment of versican is adequate for binding to HA and LP, whereas A and B-B' of aggrecan bound to LP and HA, respectively. BIAcore trade mark analyses showed that the A subdomain of versican G1 enhances HA binding but has a negligible effect on LP binding. Overlay sensorgrams demonstrated that versican G1 or its B-B' segment forms a complex with both HA and LP. We generated a molecular model of the B-B' segment, in which a deletion and an insertion of B' and B are critical for stable structure and HA binding. These results provide important insights into the mechanisms of formation of the proteoglycan aggregate and HA binding of molecules containing the link module.

    The Journal of biological chemistry 2003;278;42;41205-12

  • A hyaluronan binding link protein gene family whose members are physically linked adjacent to chondroitin sulfate proteoglycan core protein genes: the missing links.

    Spicer AP, Joo A and Bowling RA

    Center for Extracellular Matrix Biology, Texas A&M University System Health Science Center, Institute of Biosciences and Technology, Houston, Texas 77030, USA. aspicer@ibt.tamu.edu

    We describe a vertebrate hyaluronan and proteoglycan binding link protein gene family (HAPLN), consisting of four members including cartilage link protein. The encoded proteins share 45-52% overall amino acid identity. In contrast to the average sequence identity between family members, the sequence conservation between vertebrate species was very high. Human and mouse link proteins share 81-96% amino acid sequence identity. Two of the four link protein genes (HAPLN2 and HAPLN4) were restricted in expression to the brain/central nervous system, while one of the four genes (HAPLN3) was widely expressed. Genomic structures revealed that all four HAPLN genes were similar in exon-intron organization and were also similar in genomic organization to the 5' exons for the CSPG core protein genes. Strikingly, all four HAPLN genes were located immediately adjacent to the four CSPG core protein genes creating four pairs of CSPG-HAPLN genes within the mammalian genome. Furthermore, the two brain-specific HAPLN genes (HAPLN2 and HAPLN4) were physically linked to the brain-specific CSPG genes encoding brevican and neurocan, respectively. The tight physical association of the HAPLN and CSPG genes supports a hypothesis that the first HAPLN gene arose as a partial gene duplication event from an ancestral CSPG gene. There is some degree of coordinated expression of each gene pair. Collectively, the four HAPLN genes are expressed by most tissue types, reflecting the fundamental importance of the hyaluronan-dependent extracellular matrix to tissue architecture and function in vertebrate species. Comparison of the genomic structures for the HAPLN, CSPG genes and other members of the link module superfamily provide strong support for a common evolutionary origin from an ancestral gene containing one link module encoding exon.

    The Journal of biological chemistry 2003;278;23;21083-91

  • Production of cartilage link protein by human granulosa-lutein cells.

    Sun GW, Kobayashi H, Suzuki M, Kanayama N and Terao T

    Department of Obstetrics and Gynecology, Hamamatsu University School of Medicine, Shizuoka 431-3192, Japan.

    Link protein (LP), an extracellular matrix protein in cartilage, stabilizes aggregates of hyaluronic acid (HA) and proteoglycans, including aggrecan and inter-alpha-trypsin inhibitor (ITI). We have shown previously that cartilage LP is present in the maturing rat and mouse ovary. In the present study, we have employed immunohistochemistry to examine the anatomical distribution of cartilage LP in the human ovary. The expression of cartilage LP was selectively detected in the cells within the granulosa compartment of the preovulatory dominant follicle. The HA-positive granulosa-lutein cells were found to be a cartilage LP-positive subpopulation. We subsequently studied the in vitro expression of cartilage LP in cultured human granulosa-lutein cells obtained at oocyte retrieval for in vitro fertilization. Analysis of cultured cells by enzyme-linked immunoaffinity assay, Western blotting and immunofluorescence microscopy revealed that gonadotropin stimulates cartilage LP production. Time-course studies indicated that the cartilage LP production was induced as early as with gonadotropin stimulation for 2 h, and the effect was sustained up to 8 h. Western blot analysis further revealed the presence of the macroaggregates composed of HA, ITI and cartilage LP in the gonadotropin-stimulated granulosa-lutein cell extracts. Collectively, the present results raise the possibility that cartilage LP forms extracellular structures that may have a regulatory function in the developing follicle in the human ovary.

    The Journal of endocrinology 2002;175;2;505-15

  • Fibrocartilage in the transverse ligament of the human atlas.

    Milz S, Schlüter T, Putz R, Moriggl B, Ralphs JR and Benjamin M

    Anatomische Anstalt, Ludwig-Maximilians-Universität, München, Germany. milz@anat.med.uni-muenchen.de

    Immunohistochemical investigation.

    Objective: To determine whether molecules typical of articular cartilage are present in the transverse ligament and whether the ligament may be a target for an autoimmune response in rheumatoid arthritis.

    In chronic rheumatoid arthritis there is often a marked instability of the atlantoaxial complex, and the transverse ligament can show degenerative changes that compromise its mechanical function. In some rheumatoid patients there can be an autoimmune response to cartilage link protein, aggrecan, and Type II collagen.

    Methods: Transverse ligaments were removed from 13 cadavers and fixed in 90% methanol. Cryosections were immunolabeled with antibodies against proteoglycans (aggrecan, link protein, and versican), glycosaminoglycans (chondroitin-4-sulfate, chondroitin-6-sulfate, dermatan sulfate, and keratan sulfate), and collagens (Types I, II, III, and VI).

    Results: Labeling for aggrecan and link protein was characteristic of the fibrocartilages, but versican was only detected in the fibrous regions. Equally, Types I, III, and VI collagens and keratan, dermatan, and chondroitin-4-sulfates were found throughout the ligament, but labeling for Type II collagen and chondroitin-6-sulfate was restricted to the fibrocartilages.

    Conclusion: The presence of molecules typical of articular cartilage (aggrecan, link protein, and Type II collagen) in the transverse ligament explains why it can be a target for destruction in rheumatoid arthritis and also suggests that it is subject to constant compression against the dens rather than only at the extremes of movement.

    Funded by: NICHD NIH HHS: N01-HD-7-3263

    Spine 2001;26;16;1765-71

  • Glycation induced crosslinking of link proteins, in vivo and in vitro.

    Pokharna HK and Pottenger LA

    Section of Orthopeadic Surgery, University of Chicago Medical Center, Chicago, Illinois 60637, USA. hpokharn@surgery.bsd.uchicago.edu

    Objective: Reducing sugars have the ability to crosslink proteins through creation of advanced glycosylated end products (AGE). In this study, we determined the ability of AGE to induce crosslinking of link proteins and aggrecan proteoglycans.

    Methods: Aggrecan proteoglycans and link proteins were purified from adult human articular cartilage and from young bovine nasal cartilage for in vivo and in vitro studies, respectively. In vitro studies concerned incubation of aggrecan aggregates or link proteins with ribose under physiological conditions. After 30 days, aggregates were centrifuged dissociatively to obtain aggrecan monomers and link proteins. Aggrecan monomers were analyzed by immunoblot assay. Incubated link proteins were analyzed by SDS-PAGE and Sephacryl-200 column chromatography.

    Results: After extensive purification, adult human cartilage aggrecan continued to show the presence of link protein antigens by immunoblot analysis. Immunoblot analysis of purified aggrecan derived from ribose-treated aggregates also showed the presence of link protein antigens. Ribose treatment of link protein lead to polymerization that was confirmed by Sephacryl-200.

    Conclusions: These studies suggest that human link proteins tend to become crosslinked to aggrecan in adult cartilage. A likely cause of the crosslinking is formation of AGE due to reducing sugars.

    Funded by: NICHD NIH HHS: N01-HD-7-3263

    The Journal of surgical research 2000;94;1;35-42

  • The brain link protein-1 (BRAL1): cDNA cloning, genomic structure, and characterization as a novel link protein expressed in adult brain.

    Hirakawa S, Oohashi T, Su WD, Yoshioka H, Murakami T, Arata J and Ninomiya Y

    Department of Molecular Biology and Biochemistry, Okayama University Medical School, Okayama, 700-8558, Japan.

    We report here molecular cloning and expression analysis of the gene for a novel human brain link protein-1 (BRAL1) which is predominantly expressed in brain. The predicted open reading frame of human brain link protein-1 encoded a polypeptide of 340 amino acids containing three protein modules, the immunoglobulin-like fold and proteoglycan tandem repeat 1 and 2 domains, with an estimated mass of 38 kDa. The brain link protein-1 mRNA was exclusively present in brain. When analyzed during mouse development, it was detected solely in the adult brain. Concomitant expression pattern of mRNAs for brain link protein-1 and various lectican proteoglycans in brain suggests a possibility that brain link protein-1 functions to stabilize the binding between hyaluronan and brevican. The human BRAL1 gene contained 7 exons and spanned approximately 6 kb. The entire immunoglobulin-like fold was encoded by a single exon and the proteoglycan tandem repeat 1 and 2 domains were encoded by a single and two exons, respectively. The deduced amino acid sequence of human brain link protein-1 exhibited 45% identity with human cartilage link protein-1 (CRTL1), previously reported as link protein to stabilize aggregates of aggrecan and hyaluronan in cartilage. These results suggest that brain link protein-1 may have distinct function from cartilage link protein-1 and play specific roles, especially in the adult brain.

    Biochemical and biophysical research communications 2000;276;3;982-9

  • Refined genetic and physical localization of the Wagner disease (WGN1) locus and the genes CRTL1 and CSPG2 to a 2- to 2.5-cM region of chromosome 5q14.3.

    Perveen R, Hart-Holden N, Dixon MJ, Wiszniewski W, Fryer AE, Brunner HG, Pinkners AJ, van Beersum SE and Black GC

    University Department of Medical Genetics and Regional Genetic Service, St. Mary's Hospital, Hathersage Road, Manchester, M13 OJH, United Kingdom.

    Wagner syndrome (WGN1; MIM 143200), an autosomal dominant vitreoretinopathy characterized by chorioretinal atrophy, cataract, and retinal detachment, is linked to 5q14.3. Other vitreoretinopathies without systemic stigmata, including erosive vitreoretinopathy, are also linked to this region and are likely to be allelic. Within the critical region lie genes encoding two extracellular macromolecules, link protein (CRTL1) and versican (CSPG2), which are important in binding hyaluronan, a significant component of the mammalian vitreous gel, and which therefore represent excellent candidates for Wagner syndrome. Genetic mapping presented here in two further families reduces the critical region to approximately 2 cM. Subsequent refinement of the physical map allows ordering of known polymorphic microsatellites and excludes CRTL1 as a likely candidate for the disorder. CSPG2 is shown to lie within the critical region; however, analysis of the complete coding region of the mature peptide reveals no clear evidence that it is the gene underlying WGN1.

    Funded by: Wellcome Trust

    Genomics 1999;57;2;219-26

  • Autoimmunity to cartilage link protein in patients with rheumatoid arthritis and ankylosing spondylitis.

    Guerassimov A, Zhang Y, Banerjee S, Cartman A, Webber C, Esdaile J, Fitzcharles MA and Poole AR

    Joint Diseases Laboratory, Shriners Hospital for Children, McGill University, Montreal, Quebec, Canada. aguerassimov@shriners.mcgill.CA

    Objective: To determine whether patients with rheumatoid arthritis (RA) and ankylosing spondylitis (AS) express cellular immunity to cartilage link protein (LP).

    Methods: LP was purified from human fetal epiphyseal and bovine adult nasal cartilage. It was used in proliferation assays with the peripheral blood lymphocytes (PBL) isolated from 83 patients with RA, 21 patients with AS, and 30 healthy controls.

    Results: Patients with RA (34%) and AS (71%) expressed a significantly higher prevalence of cellular immune responses to human LP compared with the healthy control group (13%). Such significant differences were not observed for bovine LP. Half the patients with RA responding to LP exhibited cellular immunity to both human and bovine protein. In the AS group, PBL from a majority of responders to LP recognized only human LP.

    Conclusion: These data suggest that LP is a potential autoantigen in the development of RA and AS and that cellular immune reactivity to common and distinct LP epitopes in patients with RA and AS may play a role in the pathogenesis of these diseases.

    The Journal of rheumatology 1998;25;8;1480-4

  • Human link protein gene: structure and transcription pattern in chondrocytes.

    Dudhia J, Bayliss MT and Hardingham TE

    Kennedy Institute of Rheumatology, Hammersmith, London, U.K.

    We have examined the genomic organization and the transcription unit for the human link protein gene from genomic clones and RNA prepared from human cartilage over a wide age range. Five exons cover the gene which is greater than 60 kbp. Primer extension and S1 nuclease protection analysis revealed transcription initiation to be 315 bases upstream from the translation initiation codon in RNA derived from cartilage samples ranging from fetal to 53 years of age. The first exon size therefore is 289 bp and examination of the 5' flanking sequence indicated a lack of a TATA box in close proximity to the transcription start, although a TATAA-like motif (TCTAA) was present at -75 bp. Such a sequence at a similar distance can serve as a promoter in the chicken link protein gene. The large first exon of 289 bp is similar to that of the chicken but contrasts with that described previously for human (96 bp) and rat (62 bp). We also analysed human link protein mRNA by PCR for the presence of an alternatively spliced exon that is present in rat mRNA in low abundance, but could not detect such transcripts. Equine and porcine mRNA contained this spliced form but the results suggested that this was expressed as a rare transcript.

    The Biochemical journal 1994;303 ( Pt 1);329-33

  • Matrix metalloproteinases cleave at two distinct sites on human cartilage link protein.

    Nguyen Q, Murphy G, Hughes CE, Mort JS and Roughley PJ

    Strangeways Research Laboratory, Warts Causeway, Cambridge, U.K.

    The actions of human recombinant stromelysins-1 and -2, collagenase, gelatinases A and B and matrilysin on neonatal human proteoglycan aggregates were examined. With the exception of gelatinase B, aggrecan was degraded extensively by most metalloproteinases studied, whereas link protein showed only limited proteolysis. Sequencing studies of modified link protein components revealed that stromelysins-1 and -2, gelatinases A and B and collagenase cleaved specifically between His16 and Ile17, and matrilysin, stromelysin-2 and gelatinase A cleaved between Leu25 and Leu26. Cleavage at the former bond generated a link protein component with the same N-terminus as that isolated from newborn human cartilage. Based on previously determined in situ cleavage sites it is evident that matrix metalloproteinases are not solely responsible for the accumulation of link protein degradation products in adult human cartilage, indicating that additional proteolytic agents are involved in the normal catabolism of human cartilage matrix.

    Funded by: Wellcome Trust

    The Biochemical journal 1993;295 ( Pt 2);595-8

  • Distribution of cartilage proteoglycan (aggrecan) core protein and link protein gene expression during human skeletal development.

    Mundlos S, Meyer R, Yamada Y and Zabel B

    Department of Pediatrics, Johannes-Gutenberg-Universität, Mainz, F.R.G.

    The distribution of cartilage proteoglycan core protein (aggrecan) and cartilage proteoglycan link protein was investigated by in situ hybridization during different stages of human skeletal development. Aggrecan and link protein expression were confined to chondrocytes of the developing skeleton and other cartilaginous structures. Distribution and intensity of the signal was identical with aggrecan as compared to link protein probes. Parallel to the calcification of cartilaginous matrix, chondrocytes of this area lost the expression of aggrecan and link protein specific mRNA and stayed negative throughout the following stages of skeletal development. Highest expression was found in the lower proliferative and upper hypertrophic zone whereas the resting zone showed less expression. Aggrecan gene expression was additionally investigated in iliac crest biopsies of 3 patients with pseudoachondroplasia and compared to age-matched controls. Distribution and intensity of staining revealed no abnormalities. Thus, the phenotypic changes during chondrocyte maturation are accompanied by distinct changes in aggrecan and link protein gene expression. This pattern was maintained in the growth plate of patients with pseudoachondroplasia.

    Matrix (Stuttgart, Germany) 1991;11;5;339-46

  • Characterization of the promoter for the rat and human link protein gene.

    Rhodes C, Savagner P, Line S, Sasaki M, Chirigos M, Doege K and Yamada Y

    Laboratory of Developmental Biology, National Institute of Dental Research, National Institutes of Health, Bethesda, MD 20892.

    We have isolated the 5'-end of the gene for the rat and human link protein by screening genomic libraries with oligonucleotides corresponding to the 5'-cDNA sequence. Several overlapping clones were isolated for the human link protein gene, while only one clone was obtained for the rat. All the clones contained a single exon of which the sequence was identical to the most 5'-end of the rat and human cDNAs. Transcription initiation sites for the rat link gene were identified by primer extension and S1 protection analysis using total RNA from the rat Swarm chondrosarcoma. Transcriptional initiation sites for the human link gene were determined by specific primer extension of RNA from human fetal cartilage. Comparison of 1500 bp of 5'-flanking sequence between the rat and human link protein genes showed strong sequence conservation near the start site of transcription with 80% overall identity. Analysis of the 5'-flanking regions also revealed a large inverted repeat consisting of repeating purine-pyrimidine, which has the potential to form left-handed Z-DNA. Transcriptional regulation of the link protein gene was studied by coupling either 7.0 kb or 0.85 kb of 5'-flanking rat DNA to the chloramphenicol acetyltransferase (CAT) gene followed by transfection into chick embryonic chondrocytes (CEC) and HeLa cells. Both constructs had considerable CAT activity in CEC cells and less activity in HeLa cells. Furthermore, inclusion of a DNA fragment from the first intron increased relative CAT activity in both of these cell types. The increased activity from the first intron was shown to be orientation independent in CEC. These results indicate the presence of positive cisacting regulatory elements in both the promoter and first intron of the rat gene for link protein.

    Nucleic acids research 1991;19;8;1933-9

  • Complete amino acid sequence of human cartilage link protein (CRTL1) deduced from cDNA clones and chromosomal assignment of the gene.

    Osborne-Lawrence SL, Sinclair AK, Hicks RC, Lacey SW, Eddy RL, Byers MG, Shows TB and Duby AD

    Harold C. Simmons Arthritis Research Center, University of Texas Southwestern Medical Center, Dallas 75235.

    Little is known about the primary amino acid structure of human cartilage link protein (CRTL1). We screened a human genomic library with a cDNA encoding the 3' untranslated region and the adjoining B1 domain of chicken link protein. One clone was isolated and characterized. A 3.5-kb EcoRI-KpnI fragment from this genomic clone that contains the human B1 exon was used to map the gene to chromosome 5q13----q14.1. The same fragment was used to screen a cDNA library prepared from mRNA of Caco-2, a human colon tumor cell line. Two overlapping clones were isolated and shown to encode all of CRTL1. The deduced amino acid sequence is 354 residues long. The amino acid sequence shows a striking degree of identity to the porcine (96%), rat (96%), and chicken (85%) link protein sequences. Furthermore, there is greater than 86% homology between the 3' untranslated region of the genes encoding human and porcine link proteins. These results indicate that there has been strong evolutionary pressure against changes in the coding and 3' untranslated regions of the gene encoding cartilage link protein.

    Funded by: NIGMS NIH HHS: GM20454

    Genomics 1990;8;3;562-7

  • The primary structure of human cartilage link protein.

    Dudhia J and Hardingham TE

    Nucleic acids research 1990;18;8;2214

  • The primary structure of human cartilage link protein.

    Dudhia J and Hardingham TE

    Kennedy Institute of Rheumatology, Division of Biochemistry, Hammersmith, London, UK.

    Nucleic acids research 1990;18;5;1292

  • Immunoglobulin fold and tandem repeat structures in proteoglycan N-terminal domains and link protein.

    Perkins SJ, Nealis AS, Dudhia J and Hardingham TE

    Department of Biochemistry and Chemistry, Royal Free Hospital School of Medicine, London, U.K.

    Detailed primary sequence and secondary structure analyses are reported for the hyaluronate binding region (G1 domain) and link protein of proteoglycan aggregates. These are based on six full or partial sequences from the chicken, pig, human, rat and bovine proteins. Determinations of a full pig and a partial human link protein sequence are reported in the Appendix. Five sequences at the N terminus in both proteins were compared with the structures of 11 variable immunoglobulin (Ig) fold domains for which crystal structures are available. Despite only modest sequence homology, a clear alignment could be proposed. Analysis of this shows that the equivalents of the first and second hypervariable segments are now significantly longer, and both proteins have N-terminal extensions that are up to 23 residues in length. Secondary structure predictions showed that these sequences could be identified with available crystal structures for the variable Ig fold. However the hydrophobic residues involved in interactions between the light and heavy chains in Igs are replaced by hydrophilic charged groups in both proteins. These results imply that both proteins are members of the Ig superfamily, but exhibit structural differences distinct from other members of this superfamily for which crystal structures are known. The proteoglycan tandem repeat (PTR) is a repeat of 99 residues that is found twice in the amino acid sequence of link protein and the proteoglycan G1 domain adjacent to the Ig fold, and also twice in the proteoglycan G2 domain. A total of 16 PTRs was available for analysis. Compositional analyses show that these are positively charged if these originate from link protein, and negatively charged if from the G1 or G2 domains. The 16 Robson secondary structure predictions for the PTRs were averaged to improve the statistics of the prediction, and checked by comparison with Chou-Fasman calculations. A strong alpha-helix prediction was found at residues 13 to 25, and several beta-strands were predicted. The overall content is 18% alpha-helix and 28% beta-sheet, with 44% of the remaining sequence being predicted as turns. These analyses show that both the proteoglycan G1 domain and link protein are constructed from two distinct globular components, which may provide the two functional roles of these proteins in proteoglycan aggregation.

    Funded by: Wellcome Trust

    Journal of molecular biology 1989;206;4;737-53

Gene lists (5)

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
L00000016 G2C Homo sapiens Human PSP Human orthologues of mouse PSP adapted from Collins et al (2006) 1121
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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