HGNC Approved Gene Symbol: GAB1
Cytogenetic location: 4q31.21 Genomic coordinates (GRCh38): 4:143,336,876-143,474,565 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 4q31.21 | ?Deafness, autosomal recessive 26 | 605428 | Autosomal recessive | 3 |
GAB1 is a member of the GAB/DOS ('Daughter of Sevenless') family of adaptor molecules, which contain a pleckstrin homology domain and potential binding sites for SH2 and SH3 domains.
Using a radioactively labeled GRB2 (108355) fusion protein to screen an expression glial tumor cDNA library, Holgado-Madruga et al. (1996) identified a cDNA encoding a deduced 694-amino acid protein, which they termed GAB1, with a molecular mass of 77 kD. The GAB1 protein shares amino acid sequence homology and several structural features with the IRS1 protein (147545). The greatest homology (31% identity) is in the pleckstrin homology domain in the N terminus of both proteins. The distal two-thirds of both proteins have numerous predicted serine/threonine phosphorylation sites and several potential phosphotyrosine sites, suggesting that, like IRS1, GAB1 is a docking protein. Northern blot analysis revealed 2 GAB1 transcripts of 4.2 and 7 kb in all tissues examined except liver, lung, and kidney. The authors suggested that the larger transcript may represent alternative splicing or a related gene. They found that GAB1 transcripts were more easily detected than those of IRS1, suggesting that GAB1 is more prevalent than IRS1.
Yousaf et al. (2018) examined expression of Gab1 in the developing mouse inner ear and at postnatal day 0 observed labeling of spiral ganglion, stria vascularis, spiral prominence, internal and external sulcus cells, and Reissner membrane. In vestibular end organs (ampulla and utricle), activity was observed only in the sensory epithelium and transition cells. Immunofluorescence confocal microscopy of inner ear cells from wildtype C57BL6/J mice showed colocalization of Gab1 and Mettl13 (617987) in the cochlear duct, spiral limbus region, efferent and afferent nerves, and in spiral ganglion neurons, with similar expression levels observed in vestibular neurons as well.
By FISH, Yamada et al. (2001) mapped the GAB1 gene to human chromosome 4q13.1 and mouse chromosome 8C3.
By Far Western blot analysis, Holgado-Madruga et al. (1996) showed that GRB2 bound to a 100-kD protein from bacterial cells transformed with the proline/serine-rich fragment of GAB1. In vitro kinase assays demonstrated that GAB1 is a direct substrate of the epidermal growth factor receptor (EGFR; 131550) and the insulin receptor (INSR; 147670). Tyrosine phosphorylation of GAB1 mediates interaction with several proteins that contain SH2 domains.
GAB1 is tyrosine phosphorylated upon stimulation of various cytokines, growth factors, and antigen receptors in cell lines and interacts with signaling molecules such as SHP2 (176876) and phosphatidylinositol 3-kinase (e.g., 171833) (Holgado-Madruga et al. (1996, 1997)).
Nakaoka et al. (2003) investigated the role of GAB1 in gp130-mediated cardiac hypertrophy. Stimulation with leukemia inhibitory factor (LIF; 159540) induced tyrosine phosphorylation of GAB1, and phosphorylated GAB1 interacted with SHP2 and p85 in cultured cardiomyocytes. Using 3 adenovirus vectors (carrying wildtype GAB1, mutated GAB1 lacking the SHP2-binding site, and beta-galactosidase), they showed that GAB1 plays a critical role in elongation of cardiomyocytes induced by LIF through interaction with SHP2, and that the interaction of GAB1 with SHP2 is involved not only in the regulation of brain natriuretic polypeptide (NPPB; 600295) and skeletal alpha-actin (ACTA1; 102610) gene expression but also in the activation of ERK5 (MAPK7; 602521) after stimulation with LIF in cardiomyocytes. Coinfection of adenovirus vectors carrying wildtype GAB1 and dominant-negative ERK5 abrogated the LIF-induced cardiomyocyte elongation. Nakaoka et al. (2003) concluded that GAB1-SHP2 interaction plays a crucial role in gp130-dependent longitudinal elongation of cardiomyocytes through activation of ERK5.
In COS-7 cells, Yousaf et al. (2018) observed that both wildtype and mutant GAB1 trafficked METTL13 (617987) to the filopodia tips, indicating their interaction. Insertion of the DFNB26 (605428) and DFNB26M (605429) variants (see MOLECULAR GENETICS) into GAB1 and METTL13 did not affect the interaction. In addition, GAB1, METTL13, and SPROUTY2 (SPRY2; 602466), 3 members of the MET (164860)/HGF (142409)-signaling pathway, formed a tripartite complex within COS-7 cells. Coimmunoprecipitation studies confirmed the interactions, and showed that wildtype or mutant METTL13, but not GAB1, was able to pull down SPROUTY2, suggesting that METTL13 interacts with both GAB1 and SPROUTY2 to form the tripartite complex.
In a large consanguineous Pakistani family (PK2) with prelingual severe to profound nonsyndromic hearing loss mapping to chromosome 4q31 (DFNB26; 605428), Yousaf et al. (2018) identified homozygosity for a missense mutation in the GAB1 gene (G116E; 604439.0001) that segregated fully with the DFNB26-linked haplotype present in both deaf and nonpenetrant hearing members of the family. In addition, within a deafness-modifier interval on chromosome 1q24 that had been shown to segregate only with nonpenetrant hearing members of the family (see DFNB26M; 605429), the authors identified heterozygosity for a missense mutation in the METTL13 gene (R544Q; 617987.0001) that segregated fully with nonpenetrance for the deafness phenotype in hearing members of the family who were homozygous for the GAB1 variant. Analysis of 37 genes in the MET (164860)/HGF (142409)-signaling pathway revealed 1 gene, SPRY2 (602466), that was significantly upregulated in deaf family members but not in the nonpenetrant individuals. Yousaf et al. (2018) suggested that differential regulation of SPRY2 might be the mechanism by which the METTL13 variant functions as a modifier to prevent deafness caused by mutation in the GAB1 gene.
To reveal the functions of Gab1 in vivo, Itoh et al. (2000) generated mice lacking Gab1 by gene targeting. Gab1-deficient embryos died in utero and displayed developmental defects in the heart, placenta, and skin, which were similar to phenotypes observed in mice lacking signals of the hepatocyte growth factor (142409), platelet-derived growth factor (e.g., 173430), and epidermal growth factor (131530) pathways. Consistent with these observations, extracellular signal-regulated kinase mitogen-activated protein kinases (ERK MAPKs) were activated at much lower levels in cells from Gab1-deficient embryos in response to these growth factors or to stimulation of the cytokine receptor gp130 (IL6ST; 600694). Itoh et al. (2000) concluded that Gab1 is a common player in a broad range of growth factor and cytokine signaling pathways linking ERK MAP kinase activation.
Vasyutina et al. (2005) found that Cxcr4 (162643)-positive muscle progenitor cells reach the anlage of the tongue in Gab1-null or Cxcr4-null mouse embryos, but not in Cxcr4/Gab1 double mutants, suggesting that these proteins interact during progenitor cell migration.
By RT-PCR, Yousaf et al. (2018) detected expression of gab1 throughout development in zebrafish. Morpholino knockdown of gab1 resulted in mild to severe developmental defects at the 10- to 12-somite stage. The gab1 morphant phenotypes were subdivided into 3 classes: mild, in which morphants showed only a defect in eye formation, ranging from malformed to completely absent; moderate, in which embryos stalled at the budding stage; and severe, in which morphants were arrested at the 50% epiboly to late epiboly stages. Morphant phenotypes could be rescued by coinjection of human wildtype GAB1 mRNA.
In 8 deaf and 7 hearing members of a large consanguineous Pakistani family (PK2) with prelingual severe-to-profound nonsyndromic hearing loss (DFNM26; 605428), originally studied by Riazuddin et al. (2000), Yousaf et al. (2018) identified homozygosity for a c.347G-A transition (c.347G-A, NM_207123) in exon 2 of the GAB1 gene, resulting in a gly116-to-glu (G116E) substitution at a highly conserved residue within the PH domain. The G116E variant was not found in 380 Pakistani and 192 Indian control chromosomes, or in the 1000 Genomes Project, NHLBI Exome Variant Server, or ExAC databases. Functional analysis of the lipid-binding function of the mutant GAB1 PH domain showed significantly lower amounts bound to phosphoinositides compared to the wildtype PH domain. In addition, phenotypes of gab1-null morphant zebrafish were partially rescued by coinjection of G116E mutant mRNA compared to wildtype GAB1, suggesting that G116E represents a hypomorphic allele. Nonpenetrant hearing members of the family were also heterozygous for a missense mutation in the METTL13 gene (617987.0001), which was not present in any of the deaf members of the family.
Holgado-Madruga, M., Emlet, D. R., Moscatello, D. K., Godwin, A. K., Wong, A. J. A Grb2-associated docking protein in EGF- and insulin-receptor signalling. Nature 379: 560-564, 1996. [PubMed: 8596638] [Full Text: https://doi.org/10.1038/379560a0]
Holgado-Madruga, M., Moscatello, D. K., Emlet, D. R., Dieterich, R., Wong, A. J. Grb2-associated binder-1 mediates phosphatidylinositol 3-kinase activation and the promotion of cell survival by nerve growth factor. Proc. Nat. Acad. Sci. 94: 12419-12424, 1997. [PubMed: 9356464] [Full Text: https://doi.org/10.1073/pnas.94.23.12419]
Itoh, M., Yoshida, Y., Nishida, K., Narimatsu, M., Hibi, M., Hirano, T. Role of Gab1 in heart, placenta, and skin development and growth factor- and cytokine-induced extracellular signal-regulated kinase mitogen-activated protein kinase activation. Molec. Cell. Biol. 20: 3695-3704, 2000. [PubMed: 10779359] [Full Text: https://doi.org/10.1128/MCB.20.10.3695-3704.2000]
Nakaoka, Y., Nishida, K., Fujio, Y., Izumi, M., Terai, K., Oshima, Y., Sugiyama, S., Matsuda, S., Koyasu, S., Yamauchi-Takihara, K., Hirano, T., Kawase, I., Hirota, H. Activation of gp130 transduces hypertrophic signal through interaction of scaffolding/docking protein Gab1 with tyrosine phosphatase SHP2 in cardiomyocytes. Circ. Res. 93: 221-229, 2003. [PubMed: 12855672] [Full Text: https://doi.org/10.1161/01.RES.0000085562.48906.4A]
Riazuddin, S., Castelein, C. M., Ahmed, Z. M., Lalwani, A. K., Mastroianni, M. A., Naz, S., Smith, T. N., Liburd, N. A., Friedman, T. B., Griffith, A. J., Riazuddin, S., Wilcox, E. R. Dominant modifier DFNM1 suppresses recessive deafness DFNB26. Nature Genet. 26: 431-434, 2000. [PubMed: 11101839] [Full Text: https://doi.org/10.1038/82558]
Vasyutina, E., Stebler, J., Brand-Saberi, B., Schulz, S., Raz, E., Birchmeier, C. CXCR4 and Gab1 cooperate to control the development of migrating muscle progenitor cells. Genes Dev. 19: 2187-2198, 2005. [PubMed: 16166380] [Full Text: https://doi.org/10.1101/gad.346205]
Yamada, K., Nishida, K., Hibi, M., Hirano, T., Matsuda, Y. Comparative FISH mapping of Gab1 and Gab2 genes in human, mouse and rat. Cytogenet. Cell Genet. 94: 39-42, 2001. [PubMed: 11701952] [Full Text: https://doi.org/10.1159/000048780]
Yousaf, R., Ahmed, Z. M., Giese, A. P. J., Morell, R. J., Lagziel, A., Dabdoub, A., Wilcox, E. R., Riazuddin, S., Friedman, T. B., Riazuddin, S. Modifier variant of METTL13 suppresses human GAB1-associated profound deafness. J. Clin. Invest. 128: 1509-1522, 2018. [PubMed: 29408807] [Full Text: https://doi.org/10.1172/JCI97350]