Alternative titles; symbols
HGNC Approved Gene Symbol: GIPC1
Cytogenetic location: 19p13.12 Genomic coordinates (GRCh38): 19:14,477,762-14,496,127 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 19p13.12 | Oculopharyngodistal myopathy 2 | 618940 | Autosomal dominant | 3 |
GIPC1 is a scaffolding protein that regulates cell surface receptor expression and trafficking (Lee et al., 2008).
Regulators of G protein signaling (e.g., RGS3; 602189) act as GTPase-activating and -enhancing proteins that bind to the alpha subunits of heterotrimeric G proteins. Although their RGS domains are diagnostic and highly homologous, RGS proteins are highly divergent at their N and C termini. GAIP (RGS19; 605071) is a membrane-anchored RGS protein located on clathrin-coated vesicles involved in membrane trafficking. By screening a rat pituitary cell library using a yeast 2-hybrid system with GAIP as bait, and by searching an EST database, De Vries et al. (1998) obtained a cDNA encoding GIPC1, which they called GIPC. The predicted 36-kD, hydrophilic GIPC1 protein contains 333 amino acids, including multiple phosphorylation sites and an 80- to 100-amino acid PDZ domain. PDZ domain-containing proteins (see DLG4; 602887) typically recognize C-terminal amino acids and are involved in protein network signaling. GIPC1 shares 96% amino acid identity with rat Gipc. Northern blot analysis detected a 1.8-kb transcript in all tissues tested, with strongest expression in pancreas, followed by skeletal muscle, brain, kidney, placenta, lung, liver, and lowest expression in heart. Expression levels did not correlate with those of GAIP. Immunoblot analysis demonstrated the presence of GIPC1 primarily in cytosolic fractions but also in membrane fractions. Immunofluorescence analysis showed expression of endogenous GIPC1 in both a diffuse and a punctate staining pattern throughout the cytoplasm.
Using a yeast 2-hybrid system, Bunn et al. (1999) isolated a cDNA encoding GIPC1, which they called GLUT1CBP (GLUT1 (SLC2A1; 138140) C-terminus-binding protein). SDS-PAGE and Western blot analyses showed expression of a 39-kD protein in all tissues tested except small intestine. Northern blot analysis revealed similar expression patterns for GIPC1 and SLC2A1, with both being expressed most strongly in brain.
Using yeast 2-hybrid analysis, De Vries et al. (1998) found that GIPC1 bound GAIP and no other RGS proteins, and that the interaction occurred between the C-terminal alanine of GAIP and the PDZ domain of GIPC1.
By yeast 2-hybrid analysis, Bunn et al. (1999) showed that C19ORF3 bound SLC2A1 through its PDZ domain. Using a yeast 2-hybrid screen for brain-interacting proteins, they determined that only SLC2A1, KIF1B, and alpha actinin-1 (ACTN1; 102575) bound C19ORF3 through its PDZ domain; myosin VI (MYO6; 600970) was shown to interact with C19ORF3, but not via the PDZ domain.
Naccache et al. (2006) found that Myo6 recruitment to uncoated endocytic vesicles in cultured mouse kidney epithelial cells was dependent on synectin. Myo6 bound a C-terminal domain of synectin, and Myo6 recruitment required the interaction between the PDZ-binding domains of engulfed receptors, such as megalin (LRP2; 600073), and the PDZ domain of synectin.
Endoglin (131195) is a TGF-beta (TGFB1; 190180) coreceptor expressed predominantly in endothelial cells. Using predominantly embryonic mouse endothelial cell lines, Lee et al. (2008) showed that endoglin and Gipc interacted directly. The interaction enhanced TGF-beta-1-induced phosphorylation of Smad1 (601595)/Smad5 (603110)/Smad8 (SMAD9; 603295), increased a Smad1/Smad5/Smad8-responsive promoter, and inhibited endothelial cell migration.
By radiation hybrid analysis and FISH, Von Kap-Herr et al. (2000) localized the GIPC1 gene to chromosome 19p13.1.
In affected members of 3 unrelated Chinese families (families 1, 7, and 8) with oculopharyngodistal myopathy-2 (OPDM2; 618940), Deng et al. (2020) identified a heterozygous trinucleotide repeat expansion in the 5-prime untranslated region (UTR) of the GIPC1 gene (GGC(n); 605072.0001). The expansion, which was found by a combination of linkage analysis, long-range sequencing, and PCR analysis, segregated with the disorder in the families.
Xi et al. (2021) identified a heterozygous trinucleotide repeat in noncoding exon 1 of the GIPC1 gene (CGG(n)) in 28 patients with OPDM2, including 18 patients from 4 unrelated families and 10 patients with sporadic disease. The expansion, which was found by a combination of linkage analysis, long-range sequencing, whole-exome sequencing, and PCR analysis in family 1, segregated with the disorder in the family. The additional patients were identified by direct analysis of the CGG repeat length in the GIPC1 gene. Repeat lengths in the patients ranged from 70 to 138. Both repeat size expansion and retraction were observed in parent-to-offspring transmission.
Chittenden et al. (2006) found that synectin-null mice were smaller than wildtype mice and had reduced numbers of arteries and an altered pattern of arterial branching in multiple vascular beds, whereas the venous system remained normal. Primary arterial, but not venous, endothelial cells from synectin-null mice showed decreased in vitro tube formation, migration, and proliferation and impaired polarization due to abnormal localization of activated Rac1 (602048). A similar defect in the arterial system was present in synectin-null zebrafish embryos.
Naccache et al. (2006) found that synectin-null mice, like megalin-null mice, showed proteinuria. Urine from synectin-null mice contained retinol-binding protein (see RBP1; 180260), a known megalin ligand. Myo6, an actin-based molecular motor involved in endocytic trafficking, was upregulated in synectin-null kidneys. Megalin expression in proximal tubules of synectin-null mouse kidneys was normal compared to wildtype, suggesting that megalin recycling is defective in synectin-null mice. Naccache et al. (2006) concluded that synectin is required for proper megalin trafficking in vivo.
In affected members of 3 unrelated Chinese families (families 1, 7, and 8) with oculopharyngodistal myopathy-2 (OPDM2; 618940), Deng et al. (2020) identified a heterozygous trinucleotide repeat expansion (GGC(n)) in exon 1 of the GIPC1 gene. Translation begins in exon 4, so the repeat expansion occurred in the 5-prime untranslated region (UTR) of the gene. The expansion, which was found by a combination of linkage analysis, long-range sequencing, and PCR analysis, segregated with the disorder in the families. Further analysis of patient cohorts identified the same heterozygous repeat expansion in 9 additional Chinese patients with sporadic disease and in 7 Japanese OPDM probands. Affected individuals had GGC repeats ranging from 73 to 164, whereas GGC repeats in controls ranged from 12 to 32. Of note, 1 unaffected individual in family 1 had a repeat expansion over 500 that was difficult to detect; DNA from this patient did not produce a 'saw-tooth pattern' on PCR analysis. These findings suggested possible incomplete penetrance. Patient skeletal muscle showed increased levels of GIPC1 mRNA, but protein levels and methylation around the repeats were similar to controls. Immunostaining showed that the GIPC1 protein was distributed in the cytoplasm of skeletal muscle in both patients and controls, but partially colocalized with p62 (SQSTM1; 601530) in rimmed vacuoles and intranuclear inclusions in patient cells. RNA sequencing of patient cells showed differential regulation of several genes. Deng et al. (2020) hypothesized that elevated GIPC1 mRNA levels with the transcribed expanded GGC repeats may result in RNA toxicity.
In 28 Chinese patients with OPDM2, including 18 patients from 4 unrelated families and 10 patients with sporadic disease, Xi et al. (2021) identified a heterozygous trinucleotide repeat expansion (CGG(n)) in noncoding exon 1 of the GIPC1 gene (NM_005716). The expansion was found by a combination of linkage analysis, whole-exome sequencing, long-range sequencing, and PCR analysis in family 1, and segregated with the disorder in the family. The additional patients were identified by direct analysis of the CGG repeat length in the GIPC1 gene. Repeat lengths in the patients ranged from 70 to 138.
Bunn, R. C., Jensen, M. A., Reed, B. C. Protein interactions with the glucose transporter binding protein GLUT1CBP that provide a link between GLUT1 and the cytoskeleton. Molec. Biol. Cell 10: 819-832, 1999. [PubMed: 10198040] [Full Text: https://doi.org/10.1091/mbc.10.4.819]
Chittenden, T. W., Claes, F., Lanahan, A. A., Autiero, M., Palac, R. T., Tkachenko, E. V., Elfenbein, A., Ruiz de Almodovar, C., Dedkov, E., Tomanek, R., Li, W., Westmore, M., Singh, J., Horowitz, A., Mulligan-Kehoe, M. J., Moodie, K. L., Zhuang, Z. W., Carmeliet, P., Simons, M. Selective regulation of arterial branching morphogenesis by synectin. Dev. Cell 10: 783-795, 2006. [PubMed: 16740480] [Full Text: https://doi.org/10.1016/j.devcel.2006.03.012]
De Vries, L., Lou, X., Zhao, G., Zheng, B., Farquhar, M. G. GIPC, a PDZ domain containing protein, interacts specifically with the C terminus of RGS-GAIP. Proc. Nat. Acad. Sci. 95: 12340-12345, 1998. [PubMed: 9770488] [Full Text: https://doi.org/10.1073/pnas.95.21.12340]
Deng, J., Yu, J., Li, P., Luan, X., Cao, L., Zhao, J., Yu, M., Zhang, W., Lv, H., Xie, Z., Meng, L., Zheng, Y., and 22 others. Expansion of GGC repeat in GIPC1 is associated with oculopharyngodistal myopathy. Am. J. Hum. Genet. 106: 793-804, 2020. [PubMed: 32413282] [Full Text: https://doi.org/10.1016/j.ajhg.2020.04.011]
Lee, N. Y., Ray, B., How, T., Blobe, G. C. Endoglin promotes transforming growth factor beta-mediated Smad 1/5/8 signaling and inhibits endothelial cell migration through its association with GIPC. J. Biol. Chem. 283: 32527-32533, 2008. [PubMed: 18775991] [Full Text: https://doi.org/10.1074/jbc.M803059200]
Naccache, S. N., Hasson, T., Horowitz, A. Binding of internalized receptors to the PDZ domain of GIPC/synectin recruits myosin VI to endocytic vesicles. Proc. Nat. Acad. Sci. 103: 12735-12740, 2006. Note: Erratum: Proc. Nat. Acad. Sci. 103: 15272 only, 2006. [PubMed: 16908842] [Full Text: https://doi.org/10.1073/pnas.0605317103]
Von Kap-Herr, C., Kandala, G., Mann, S. S., Hart, T. C., Pettenati, M. J., Setaluri, V. Assignment of PDZ domain-containing protein GIPC gene (C19orf3) to human chromosome band 19p13.1 by in situ hybridization and radiation hybrid mapping. Cytogenet. Cell Genet. 89: 234-235, 2000. [PubMed: 10965131] [Full Text: https://doi.org/10.1159/000015621]
Xi, J., Wang, X., Yue, D., Dou, T., Wu, Q., Lu, J., Liu, Y., Yu, W., Qiao, K., Lin, J., Luo, S., Li, J., and 11 others. 5-Prime UTR CGG repeat expansion in GIPC1 is associated with oculopharyngodistal myopathy. Brain 144: 601-614, 2021. [PubMed: 33374016] [Full Text: https://doi.org/10.1093/brain/awaa426]