Alternative titles; symbols
HGNC Approved Gene Symbol: GIPC3
Cytogenetic location: 19p13.3 Genomic coordinates (GRCh38): 19:3,585,478-3,593,541 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 19p13.3 | Deafness, autosomal recessive 15 | 601869 | Autosomal recessive | 3 |
By genomic sequence analysis and RT-PCR of fetal lung RNA, Saitoh et al. (2002) obtained a full-length cDNA encoding GIPC3. The predicted 312-amino acid protein contains an N-terminal GIPC homology domain (GH1), a central PDZ domain, and a C-terminal GH2 domain. GIPC3 shares 59.9% amino acid identity with GIPC1 (605072), 55.3% identity with GIPC2 (619089), and 57.2% identity with Xenopus Kermit. Northern blot analysis detected nearly ubiquitous expression of a 4.5-kb GIPC3 transcript, with highest expression in small intestine. RNA dot blot analysis showed highest GIPC3 expression in jejunum, lymph node, parietal lobe, fetal spleen, and fetal thymus. Northern blot analysis detected GIPC3 expression in cervical, melanoma, and chronic myelogenous leukemia cancer cell lines and in 2 of 7 gastric cancer cell lines examined.
Saitoh et al. (2002) determined that the GIPC3 gene contains 6 exons.
By genomic sequence analysis, Saitoh et al. (2002) mapped the GIPC3 gene to chromosome 19p13.3.
In affected members of an Indian and a Dutch family with autosomal recessive sensorineural deafness of prelingual onset (DFNB15; 601869), Charizopoulou et al. (2011) identified 2 different homozygous mutations in the GIPC3 gene (L262R, 608792.0001 and W301X, 608792.0002, respectively). The gene was chosen for study after Charizopoulou et al. (2011) found that a mutation in the murine gene Gipc3 was responsible for autosomal recessive deafness in the mouse (see ANIMAL MODEL).
Rehman et al. (2011) identified 7 different homozygous mutations, including 1 frameshift and 6 missense, in the GIPC3 gene (see, e.g., 601869.0003-601869.0006) in affected members of 7 unrelated consanguineous Pakistani families with autosomal recessive nonsyndromic deafness, including 2 families with DFNB72 previously been reported by Ain et al. (2007). All but 1 of the mutations (R189C; 601869.0006) was located in the GH1 or GH2 domains.
By positional cloning of a mouse model (ahl5) of autosomal recessive early-onset age-related hearing loss, Charizopoulou et al. (2011) identified a homozygous G115R mutation in exon 2 of the Gipc3 gene, affecting the PDZ domain of the protein. Mutation in the Gipc3 gene was also found to underlie the murine juvenile audiogenic monogenic seizure (jams1) phenotype, in which affected mice show seizure susceptibility early in life that disappears with age. The G115R mutation caused a reduction of the Gipc3 protein. Histopathologic studies of mutant mice showed irregular structure of the stereocilia bundle of outer and inner hair cells, and late-onset degeneration of the organ of Corti starting at the base and progressing towards the apex. Concomitantly, the spiral ganglion exhibited a severe loss of neurons that was most obvious at the base and the mid-apical region of the cochlea. These data suggest that Gipc3 is required for postnatal maturation of the hair bundle and long-term survival of hair cells and spiral ganglion. Mutant mice showed defects in mechanotransduction in both inner and outer hair cells that was associated with defects in potassium channel activity. Audiogenic seizure susceptibility and later resistance correlated with increased and subsequent decline of the amplitude of audiogenic brainstem responses. In wildtype mice, Gipc3 was localized to the cytoplasm of inner and outer hair cells, cochlear spiral ganglion neurons, vestibular hair cells, and vestibular ganglion neurons.
In affected members of a consanguineous Indian family with autosomal recessive deafness (DFNB15; 601869) (Chen et al., 1997), Charizopoulou et al. (2011) identified a homozygous 785T-G transversion in exon 5 of the GIPC3 gene, resulting in a leu262-to-arg (L262R) substitution in a highly conserved residue in the GH2 domain. The mutation was not detected in 322 control chromosomes. The deafness was nonsyndromic and of prelingual onset.
In affected members of a Dutch family with autosomal recessive deafness (DFNB15; 601869), to which the locus DFNB95 had been assigned, Charizopoulou et al. (2011) identified a homozygous 903G-A transition in exon 6 of the GIPC3 gene, resulting in a trp301-to-ter (W301X) substitution and loss of the last 12 residues of the protein. The mutation was not found in 312 control chromosome. The hearing loss was bilateral and sensorineural with early onset apparent in infancy.
In affected members of a consanguineous Pakistani family with DFNB15 (601869), Rehman et al. (2011) identified a homozygous 1-bp duplication (685dupG) in exon 4 of the GIPC3 gene, resulting in a frameshift and premature termination of the GH2 domain. The mutation was not found in 572 control chromosomes. The family had previously been reported by Ain et al. (2007), and mapped to locus DFNB72.
In affected members of a consanguineous Pakistani family with DFNB15 (601869), Rehman et al. (2011) identified a homozygous 767G-A transition in exon 5 of the GIPC3 gene, resulting in a gly256-to-asp (G256D) substitution in a conserved residue in the GH2 domain. The mutation was not found in 572 control chromosomes. The family had previously been reported by Ain et al. (2007), and mapped to locus DFNB72.
In affected members of a consanguineous Pakistani family with DFNB15 (601869), Rehman et al. (2011) identified a homozygous 136G-A transition in exon 1 of the GIPC3 gene, resulting in a gly46-to-arg (G46R) substitution in a conserved residue in the GH1 domain. The mutation was not found in 590 control chromosomes.
In affected members of a consanguineous Pakistani family with DFNB15 (601869), Rehman et al. (2011) identified a homozygous 565C-T transition in exon 3 of the GIPC3 gene, resulting in arg189-to-cys (R189C) substitution in a conserved residue in the PDZ domain. The mutation was not found in 590 control chromosomes.
Ain, Q., Nazli, S., Riazuddin, S., Jaleel, A., Riazuddin, S. A., Zafar, A. U., Khan, S. N., Husnain, T., Griffith, A. J., Ahmed, Z. M., Friedman, T. B., Riazuddin, S. The autosomal recessive nonsyndromic deafness locus DFNB72 is located on chromosome 19p13.3. Hum. Genet. 122: 445-450, 2007. [PubMed: 17690910] [Full Text: https://doi.org/10.1007/s00439-007-0418-z]
Charizopoulou, N., Lelli, A., Schraders, M., Ray, K., Hildebrand, M. S., Ramesh, A., Srisailapathy, C. R., Oostrik, J., Admiraal, R. J. C., Neely, H. R., Latoche, J. R., Smith, R. J. H., Northup, J. K., Kremer, H., Holt, J. R., Noben-Trauth, K. Gipc3 mutations associated with audiogenic seizures and sensorineural hearing loss in mouse and human. Nature Commun. 2: 201, 2011. Note: Electronic Article. [PubMed: 21326233] [Full Text: https://doi.org/10.1038/ncomms1200]
Chen, A., Wayne, S., Bell, A., Ramesh, A., Srisailapathy, C. R., Scott, D. A., Sheffield, V. C., Van Hauwe, P., Zbar, R. I., Ashley, J., Lovett, M., Van Camp, G., Smith, R. J. New gene for autosomal recessive non-syndromic hearing loss maps to either chromosome 3q or 19p. Am. J. Med. Genet. 71: 467-471, 1997. [PubMed: 9286457]
Rehman, A. U., Gul, K., Morell, R. J., Lee, K., Ahmed, Z. M., Riazuddin, S., Ali, R. A., Shahzad, M., Jaleel, A., Andrade, P. B., Khan, S. N., Khan, S., Brewer, C. C., Ahmad, W., Leal, S. M., Riazuddin, S., Friedman, T. B. Mutations of GIPC3 cause nonsyndromic hearing loss DFNB72 but not DFNB81 that also maps to chromosome 19p. Hum. Genet. 130: 759-765, 2011. [PubMed: 21660509] [Full Text: https://doi.org/10.1007/s00439-011-1018-5]
Saitoh, T., Mine, T., Katoh, M. Molecular cloning and characterization of human GIPC3, a novel gene homologous to human GIPC1 and GIPC2. Int. J. Oncol. 20: 577-582, 2002. [PubMed: 11836571]