G2Cdb::Gene report

Gene id
Gene symbol
Homo sapiens
FYVE, RhoGEF and PH domain containing 4
G00001147 (Mus musculus)

Databases (6)

ENSG00000139132 (Ensembl human gene)
121512 (Entrez Gene)
154 (G2Cdb plasticity & disease)
FGD4 (GeneCards)
Marker Symbol
HGNC:19125 (HGNC)
Protein Sequence
Q96M96 (UniProt)

Synonyms (4)

  • CMT4H
  • ZFYVE6
  • frabin

Literature (15)

Pubmed - other

  • Further evidence that mutations in FGD4/frabin cause Charcot-Marie-Tooth disease type 4H.

    Fabrizi GM, Taioli F, Cavallaro T, Ferrari S, Bertolasi L, Casarotto M, Rizzuto N, Deconinck T, Timmerman V and De Jonghe P

    Section of Clinical Neurology, Department of Neurological and Visual Sciences, University of Verona, Ospedale Policlinico G.B. Rossi, P.le L.A. Scuro 10, 37134 Verona, Italy. gianmaria.fabrizi@univr.it

    Background: Autosomal recessive demyelinating Charcot-Marie-Tooth neuropathy type 4H (CMT4H) manifests early onset, severe functional impairment, deforming scoliosis, and myelin outfoldings in the nerve biopsy. Mutations in the FGD4 gene encoding the Rho-GTPase guanine-nucleotide-exchange-factor frabin were reported in five families.

    Objective: To characterize a novel mutation in FGD4 and describe the related phenotype.

    Methods: A 20-year-old woman born of healthy consanguineous parents and affected with early-onset peroneal muscular atrophy underwent standard clinical, electrophysiologic, and pathologic (sural nerve biopsy) investigations. Mutational analysis of FGD4 was performed by direct sequencing of genomic DNA. Transcriptional analysis was done by reverse transcriptase PCR on leukocyte RNA.

    Results: The proband disclosed a moderately severe, scarcely progressive CMT, markedly slowed nerve conduction velocities, and a demyelinating neuropathy characterized by prominent myelin outfoldings. Mutational analysis disclosed a c.1762-2a>g transition in the splice-acceptor site of intron 14, which was predicted to cause a truncated frabin (p.Tyr587fsX14).

    Conclusions: The report confirms genetic heterogeneity of FGD4, demonstrates that CMT4H has variable functional impairment, and suggests that frabin plays a crucial role during myelin formation.

    Funded by: Telethon: GUP05007

    Neurology 2009;72;13;1160-4

  • A novel Frabin (FGD4) nonsense mutation p.R275X associated with phenotypic variability in CMT4H.

    Houlden H, Hammans S, Katifi H and Reilly MM

    Institute of Neurology, Queen Square, London WC1N3BG, UK. h.houlden@ion.ucl.ac.uk

    Background: Charcot Marie Tooth (CMT) disease is a heterogeneous group of inherited peripheral motor and sensory neuropathies. CMT4H is an early onset autosomal recessive demyelinating neuropathy. The locus responsible for CMT4H was assigned to chromosome 12p11.21-q13.11 by homozygosity mapping and mutations in the Frabin gene (FGD4 Rho GDP/GTP exchange factor) were subsequently identified in six families.

    Methods: We sequenced the Frabin gene in a cohort of 12 UK CMT families with clinically defined autosomal recessive demyelinating neuropathy.

    Results: We identified a novel homozygous Frabin p.R275X mutation in a family from Northern Ireland. The two affected cases in this family had a very slowly progressive neuropathy with both cases remaining ambulant into middle age. Examination of mRNA from lymphoblasts showed that this stop mutation caused very little nonsense mediated mRNA decay and the predominant mRNA species was the mutant form that is likely to be translated into a truncated protein.

    Conclusions: This work extends the understanding of the pathogenesis of Frabin mutation-associated Charcot Marie Tooth (CMT) 4H and suggests that mutations in Frabin should also be considered in ambulant adults with CMT1.

    Funded by: Department of Health; Medical Research Council: G0601943, G108/638

    Neurology 2009;72;7;617-20

  • Differential protein expression by dendritic cells from atopic and non-atopic individuals after stimulation by the major house dust mite allergen Der p 1.

    Horlock C, Shakib F, Jones NS, Sewell HF and Ghaemmaghami AM

    Institute of Infection, Immunity and Inflammation, School of Molecular Medical Sciences and Biomedical Research Unit, University of Nottingham, Nottingham, UK.

    Background: Dendritic cells (DCs) are sentinels of the immune system and are known to play a key role in allergic responses. However, it is not clear how DCs that have been exposed to an allergen support Th2 type immune responses. It is possible that DCs from atopic individuals are inherently programmed to support allergic disease, or it is the exposure of dendritic cells to allergens that is key to the development of allergic sensitisation.

    Methods: We used 2D gel electrophoresis and MALDI mass spectrometry to compare the proteome of DCs from atopic and non-atopic individuals in both the resting state and after stimulation with the major house dust mite allergen Der p 1.

    Results: Our data show that unstimulated DCs from atopic and non-atopic individuals are very similar at the whole cell proteome level, showing few differentially expressed proteins. However, upon stimulation with Der p 1, a number of additional proteins are differentially expressed, and of these several were of potential relevance to Th2 cell differentiation and the allergic response, including GTP-binding regulatory protein Gi alpha-2, frabin and cathepsin D.

    Conclusion: Whilst there are inherent differences between DCs from atopic and non-atopic individuals, it seems that exposure to allergen plays a key role in differential expression of proteins by these key immune cells. Further studies should now focus on establishing the biological relevance of these proteins as biomarkers in house dust mite allergy and their role in allergen induced Th2 cell differentiation.

    International archives of allergy and immunology 2009;150;3;237-51

  • Mutations in FGD4 encoding the Rho GDP/GTP exchange factor FRABIN cause autosomal recessive Charcot-Marie-Tooth type 4H.

    Delague V, Jacquier A, Hamadouche T, Poitelon Y, Baudot C, Boccaccio I, Chouery E, Chaouch M, Kassouri N, Jabbour R, Grid D, Mégarbané A, Haase G and Lévy N

    INSERM U491, Génétique Médicale et Développement, Faculté de Médecine de la Timone, Marseille, France. valerie.delague@medecine.univ-mrs.fr

    Charcot-Marie-Tooth (CMT) disorders are a clinically and genetically heterogeneous group of hereditary motor and sensory neuropathies characterized by muscle weakness and wasting, foot and hand deformities, and electrophysiological changes. The CMT4H subtype is an autosomal recessive demyelinating form of CMT that was recently mapped to a 15.8-Mb region at chromosome 12p11.21-q13.11, in two consanguineous families of Mediterranean origin, by homozygosity mapping. We report here the identification of mutations in FGD4, encoding FGD4 or FRABIN (FGD1-related F-actin binding protein), in both families. FRABIN is a GDP/GTP nucleotide exchange factor (GEF), specific to Cdc42, a member of the Rho family of small guanosine triphosphate (GTP)-binding proteins (Rho GTPases). Rho GTPases play a key role in regulating signal-transduction pathways in eukaryotes. In particular, they have a pivotal role in mediating actin cytoskeleton changes during cell migration, morphogenesis, polarization, and division. Consistent with these reported functions, expression of truncated FRABIN mutants in rat primary motoneurons and rat Schwann cells induced significantly fewer microspikes than expression of wild-type FRABIN. To our knowledge, this is the first report of mutations in a Rho GEF protein being involved in CMT.

    American journal of human genetics 2007;81;1;1-16

  • Peripheral nerve demyelination caused by a mutant Rho GTPase guanine nucleotide exchange factor, frabin/FGD4.

    Stendel C, Roos A, Deconinck T, Pereira J, Castagner F, Niemann A, Kirschner J, Korinthenberg R, Ketelsen UP, Battaloglu E, Parman Y, Nicholson G, Ouvrier R, Seeger J, De Jonghe P, Weis J, Krüttgen A, Rudnik-Schöneborn S, Bergmann C, Suter U, Zerres K, Timmerman V, Relvas JB and Senderek J

    Institute of Cell Biology, ETH Zürich, Schafmattstrasse 18, CH-8093 Zürich, Switzerland. claudia.stendel@cell.biol.ethz.ch

    GTPases of the Rho subfamily are widely involved in the myelination of the vertebrate nervous system. Rho GTPase activity is temporally and spatially regulated by a set of specific guanine nucleotide exchange factors (GEFs). Here, we report that disruption of frabin/FGD4, a GEF for the Rho GTPase cell-division cycle 42 (Cdc42), causes peripheral nerve demyelination in patients with autosomal recessive Charcot-Marie-Tooth (CMT) neuropathy. These data, together with the ability of frabin to induce Cdc42-mediated cell-shape changes in transfected Schwann cells, suggest that Rho GTPase signaling is essential for proper myelination of the peripheral nervous system.

    American journal of human genetics 2007;81;1;158-64

  • Homozygosity mapping of autosomal recessive demyelinating Charcot-Marie-Tooth neuropathy (CMT4H) to a novel locus on chromosome 12p11.21-q13.11.

    De Sandre-Giovannoli A, Delague V, Hamadouche T, Chaouch M, Krahn M, Boccaccio I, Maisonobe T, Chouery E, Jabbour R, Atweh S, Grid D, Mégarbané A and Lévy N

    Journal of medical genetics 2005;42;3;260-5

  • Phosphatidylinositol 3-kinase and frabin mediate Cryptosporidium parvum cellular invasion via activation of Cdc42.

    Chen XM, Splinter PL, Tietz PS, Huang BQ, Billadeau DD and LaRusso NF

    The Center for Basic Research in Digestive Diseases, Division of Gastroenterology and Hepatology, Mayo Medical School, Clinic and Foundation, Rochester, Minnesota 55905, USA.

    Cryptosporidium parvum invades target epithelia via a mechanism that involves host cell actin reorganization. We previously demonstrated that C. parvum activates the Cdc42/neural Wiskott-Aldrich syndrome protein network in host cells resulting in actin remodeling at the host cell-parasite interface, thus facilitating C. parvum cellular invasion. Here, we tested the role of phosphatidylinositol 3-kinase (PI3K) and frabin, a guanine nucleotide exchange factor specific for Cdc42 in the activation of Cdc42 during C. parvum infection of biliary epithelial cells. We found that C. parvum infection of cultured human biliary epithelial cells induced the accumulation of PI3K at the host cell-parasite interface and resulted in the activation of PI3K in infected cells. Frabin also was recruited to the host cell-parasite interface, a process inhibited by two PI3K inhibitors, wortmannin and LY294002. The cellular expression of either a dominant negative mutant of PI3K (PI3K-Deltap85) or functionally deficient mutants of frabin inhibited C. parvum-induced Cdc42 accumulation at the host cell-parasite interface. Moreover, LY294002 abolished C. parvum-induced Cdc42 activation in infected cells. Inhibition of PI3K by cellular overexpression of PI3K-Deltap85 or by wortmannin or LY294002, as well as inhibition of frabin by various functionally deficient mutants, decreased C. parvum-induced actin accumulation and inhibited C. parvum cellular invasion. In contrast, the overexpression of the p85 subunit of PI3K promoted C. parvum invasion. Our data suggest that an important component of the complex process of C. parvum invasion of target epithelia results from the ability of the organism to trigger host cell PI3K/frabin signaling to activate the Cdc42 pathway, resulting in host cell actin remodeling at the host cell-parasite interface.

    Funded by: NIDDK NIH HHS: DK24031, DK57993

    The Journal of biological chemistry 2004;279;30;31671-8

  • Complete sequencing and characterization of 21,243 full-length human cDNAs.

    Ota T, Suzuki Y, Nishikawa T, Otsuki T, Sugiyama T, Irie R, Wakamatsu A, Hayashi K, Sato H, Nagai K, Kimura K, Makita H, Sekine M, Obayashi M, Nishi T, Shibahara T, Tanaka T, Ishii S, Yamamoto J, Saito K, Kawai Y, Isono Y, Nakamura Y, Nagahari K, Murakami K, Yasuda T, Iwayanagi T, Wagatsuma M, Shiratori A, Sudo H, Hosoiri T, Kaku Y, Kodaira H, Kondo H, Sugawara M, Takahashi M, Kanda K, Yokoi T, Furuya T, Kikkawa E, Omura Y, Abe K, Kamihara K, Katsuta N, Sato K, Tanikawa M, Yamazaki M, Ninomiya K, Ishibashi T, Yamashita H, Murakawa K, Fujimori K, Tanai H, Kimata M, Watanabe M, Hiraoka S, Chiba Y, Ishida S, Ono Y, Takiguchi S, Watanabe S, Yosida M, Hotuta T, Kusano J, Kanehori K, Takahashi-Fujii A, Hara H, Tanase TO, Nomura Y, Togiya S, Komai F, Hara R, Takeuchi K, Arita M, Imose N, Musashino K, Yuuki H, Oshima A, Sasaki N, Aotsuka S, Yoshikawa Y, Matsunawa H, Ichihara T, Shiohata N, Sano S, Moriya S, Momiyama H, Satoh N, Takami S, Terashima Y, Suzuki O, Nakagawa S, Senoh A, Mizoguchi H, Goto Y, Shimizu F, Wakebe H, Hishigaki H, Watanabe T, Sugiyama A, Takemoto M, Kawakami B, Yamazaki M, Watanabe K, Kumagai A, Itakura S, Fukuzumi Y, Fujimori Y, Komiyama M, Tashiro H, Tanigami A, Fujiwara T, Ono T, Yamada K, Fujii Y, Ozaki K, Hirao M, Ohmori Y, Kawabata A, Hikiji T, Kobatake N, Inagaki H, Ikema Y, Okamoto S, Okitani R, Kawakami T, Noguchi S, Itoh T, Shigeta K, Senba T, Matsumura K, Nakajima Y, Mizuno T, Morinaga M, Sasaki M, Togashi T, Oyama M, Hata H, Watanabe M, Komatsu T, Mizushima-Sugano J, Satoh T, Shirai Y, Takahashi Y, Nakagawa K, Okumura K, Nagase T, Nomura N, Kikuchi H, Masuho Y, Yamashita R, Nakai K, Yada T, Nakamura Y, Ohara O, Isogai T and Sugano S

    Helix Research Institute, 1532-3 Yana, Kisarazu, Chiba 292-0812, Japan.

    As a base for human transcriptome and functional genomics, we created the "full-length long Japan" (FLJ) collection of sequenced human cDNAs. We determined the entire sequence of 21,243 selected clones and found that 14,490 cDNAs (10,897 clusters) were unique to the FLJ collection. About half of them (5,416) seemed to be protein-coding. Of those, 1,999 clusters had not been predicted by computational methods. The distribution of GC content of nonpredicted cDNAs had a peak at approximately 58% compared with a peak at approximately 42%for predicted cDNAs. Thus, there seems to be a slight bias against GC-rich transcripts in current gene prediction procedures. The rest of the cDNAs unique to the FLJ collection (5,481) contained no obvious open reading frames (ORFs) and thus are candidate noncoding RNAs. About one-fourth of them (1,378) showed a clear pattern of splicing. The distribution of GC content of noncoding cDNAs was narrow and had a peak at approximately 42%, relatively low compared with that of protein-coding cDNAs.

    Nature genetics 2004;36;1;40-5

  • Ten years on: mediation of cell death by the common neurotrophin receptor p75(NTR).

    Rabizadeh S and Bredesen DE

    The Buck Institute for Age Research, 8001 Redwood Blvd, Novato, CA 94945-1400, USA. srabizadeh@buckinstitute.org

    The common neurotrophin receptor p75(NTR) remains one of the most enigmatic of the tumor necrosis factor receptor (TNFR) superfamily: on the one hand, it displays a death domain and has been shown to be capable of mediating programmed cell death (PCD) upon ligand binding; on the other hand, its death domain is of type II (unlike that of Fas or TNFR I), and it has also been shown to be capable of mediating cell death in response to the withdrawal of ligand. Thus, p75(NTR) may function as a death receptor-similar to Fas or TNFR I-or a dependence receptor-similar to deleted in colorectal cancer (DCC) or uncoordinated gene-5 homologues 1-3 (UNC5H1-3). Here, we review the data relating to the mediation of PCD by p75(NTR), and suggest that one reasonable model for the apparently paradoxical effects of p75(NTR) is that this receptor functions as a "quality control" in that it is capable of mediating PCD in at least four situations: (1). withdrawal of neurotrophins; (2). exposure to mismatched neurotrophins; (3). exposure to unprocessed neurotrophins; and (4). exposure of inappropriately immature cells to neurotrophins. Results to date suggest that these functions are mediated through different underlying mechanisms, and that their respective signaling pathways are cell type and co-receptor dependent.

    Cytokine & growth factor reviews 2003;14;3-4;225-39

  • NRAGE, a p75 neurotrophin receptor-interacting protein, induces caspase activation and cell death through a JNK-dependent mitochondrial pathway.

    Salehi AH, Xanthoudakis S and Barker PA

    Centre for Neuronal Survival, Montreal Neurological Institute, McGill University, 3801 University Avenue, Montreal, Quebec H3A 2B4, Canada.

    The p75 neurotrophin receptor (p75NTR) mediates signaling events leading to activation of the JNK pathway and cell death in a variety of cell types. We recently identified NRAGE, a protein that directly interacts with the p75NTR cytosolic region and facilitates p75NTR-mediated cell death. For the present study, we developed an inducible recombinant NRAGE adenovirus to dissect the mechanism of NRAGE-mediated apoptosis. Induced NRAGE expression resulted in robust activation of the JNK pathway that was not inhibited by the pharmacological mixed lineage kinase (MLK) inhibitor CEP1347. NRAGE induced cytosolic accumulation of cytochrome c, activation of Caspases-3, -9 and -7, and caspase-dependent cell death. Blocking JNK and c-Jun action by overexpression of the JNK-binding domain of JIP1 or dominant-negative c-Jun ablated NRAGE-mediated caspase activation and NRAGE-induced cell death. These findings identify NRAGE as a p75NTR interactor capable of inducing caspase activation and cell death through a JNK-dependent mitochondrial apoptotic pathway.

    The Journal of biological chemistry 2002;277;50;48043-50

  • Activation of Rac GTPase by p75 is necessary for c-jun N-terminal kinase-mediated apoptosis.

    Harrington AW, Kim JY and Yoon SO

    Neurobiotech Center and Department of Neuroscience, Ohio State University, Columbus, Ohio 43210, USA.

    The neurotrophin receptor p75 can induce apoptosis both in vitro and in vivo. The mechanisms by which p75 induces apoptosis have remained mostly unknown. Here, we report that p75 activates Rac GTPase, which in turn activates c-jun N-terminal kinase (JNK), including an injury-specific JNK3, in an NGF-dependent manner. N17Rac blocks this JNK activation and subsequent NGF-dependent apoptosis, indicating that activation of Rac GTPase is required for JNK activation and apoptosis induced by p75. In addition, p75-mediated Rac activation is modulated by coactivation of Trk, identifying Rac GTPase as one of the key molecules whose activity is critical for cell survival and death in neurotrophin signaling. The crucial role of the JNK pathway in p75 signaling is further confirmed by the results that blocking p75 from signaling via the JNK pathway or suppressing the JNK activity itself led to inhibition of NGF-dependent death. Together, these results indicate that the apoptotic machinery of p75 comprises Rac GTPase and JNK.

    Funded by: NINDS NIH HHS: R01 NS39472-01

    The Journal of neuroscience : the official journal of the Society for Neuroscience 2002;22;1;156-66

  • Identification of splicing variants of Frabin with partly different functions and tissue distribution.

    Ikeda W, Nakanishi H, Takekuni K, Itoh S and Takai Y

    Department of Molecular Biology and Biochemistry, Osaka University Graduate School of Medicine/Faculty of Medicine, Suita, 565-0871, Japan.

    Frabin is a GDP/GTP exchange protein for Cdc42 small G protein with actin filament-binding activity. Frabin consists of the actin filament-binding domain, the Dbl homology domain, the first pleckstrin homology domain, the FYVE-finger domain, and the second pleckstrin homology domain in this order from the N-terminus. Frabin forms filopodia through direct activation of Cdc42 and lamellipodia through indirect activation of Rac small G protein. We isolated here two smaller splicing variants of frabin and named the original one, middle-size one, and smallest one frabin-alpha, -beta, and -gamma, respectively. Frabin-beta lacked the second pleckstrin homology domain and frabin-gamma lacked the FYVE-finger domain and the second pleckstrin homology domain. These three variants were expressed in all of the tissues examined but their expression levels are different depending on tissues. In L fibroblasts, all the three variants formed filopodia. As to lamellipodia, frabin-alpha formed them; frabin-beta formed them to a small extent; and frabin-gamma did not. In MDCK epithelial cells, frabin-alpha formed microspikes but frabin-beta or -gamma did not.

    Biochemical and biophysical research communications 2001;286;5;1066-72

  • Cooperation of Cdc42 small G protein-activating and actin filament-binding activities of frabin in microspike formation.

    Ikeda W, Nakanishi H, Tanaka Y, Tachibana K and Takai Y

    Department of Molecular Biology and Biochemistry, Osaka University Graduate School of Medicine/Faculty of Medicine, Suita 565-0871, Japan.

    Frabin is a GDP/GTP exchange protein for Cdc42 with actin filament (F-actin)-binding activity. Cdc42 is a small GTP-binding protein that forms filopodia-like microspikes in a variety of cells. Expression of frabin indeed forms microspikes through at least activation of Cdc42 in MDCK cells and fibroblasts such as COS7, L, and NIH3T3 cells. However, the role of the F-actin-binding activity of frabin in the microspike formation remains unknown. We have examined here this role of frabin by expressing various frabin mutants, which have lost Cdc42-activating or F-actin-binding activity, with or without a dominant active mutant of Cdc42 in MDCK and COS7 cells. We show here that for the microspike formation, either of the Cdc42-activating and F- actin-binding activities of frabin alone is not sufficient and both the activities are necessary and that both the activities play a cooperative role in the microspike formation. The present results, together with the earlier finding that Cdc42 reorganizes the actin cytoskeleton at least through the N-WASP-Arp2/3 complex, suggest that frabin directly and indirectly reorganizes the actin cytoskeleton through its F-actin-binding and Cdc42-activating activities, respectively, in a cooperative manner, eventually leading to microspike formation.

    Oncogene 2001;20;27;3457-63

  • Frabin, a novel FGD1-related actin filament-binding protein capable of changing cell shape and activating c-Jun N-terminal kinase.

    Obaishi H, Nakanishi H, Mandai K, Satoh K, Satoh A, Takahashi K, Miyahara M, Nishioka H, Takaishi K and Takai Y

    Takai Biotimer Project, ERATO, Japan Science and Technology Corporation, c/o JCR Pharmaceuticals Co., Ltd., 2-2-10 Murotani, Nishi-ku, Kobe 651-2241, Japan.

    We purified from rat brain a novel F-actin-binding protein with a Mr of about 105,000 (p105), which was estimated by SDS-polyacrylamide gel electrophoresis. We cloned its cDNA from a rat brain cDNA library and characterized it. p105 was a protein of 766 amino acids and showed a calculated Mr of 86,449. p105 consisted of one F-actin-binding domain at the N-terminal region, one Dbl homology domain and one pleckstrin homology domain at the middle region, and one cysteine-rich domain at the C-terminal region. This domain organization of p105 was similar to that of FGD1, which has been determined to be the genetic locus responsible for faciogenital dysplasia or Aarskog-Scott syndrome. We therefore named p105 frabin (FGD1-related F-actin-binding protein). Frabin bound along the sides of F-actin and showed F-actin-cross-linking activity. Overexpression of frabin in Swiss 3T3 cells and COS7 cells induced cell shape change and c-Jun N-terminal kinase activation, respectively, as described for FGD1. Because FGD1 has been shown to serve as a GDP/GTP exchange protein for Cdc42 small G protein, it is likely that frabin is a direct linker between Cdc42 and the actin cytoskeleton.

    The Journal of biological chemistry 1998;273;30;18697-700

Gene lists (3)

Gene List Source Species Name Description Gene count
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
L00000034 G2C Homo sapiens Pocklington H3 Human orthologues of cluster 3 (mouse) from Pocklington et al (2006) 30
© 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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