GIPC3

PDZ domain-containing protein GIPC3 is a is_associated_with::protein that in humans is encoded by the GIPC3 is_associated_with::gene. GIPC3 is a member of the GIPC (GAIP-interacting protein C terminus) gene family that also includes is_associated_with::GIPC1 and is_associated_with::GIPC2. The encoded protein, GIPC3, features a centrally located is_associated_with::PDZ domain, which is flanked on each side by a single GIPC-homology domain.

Function
GIPC3 is thought to be important for acoustic signal acquisition and propagation in is_associated_with::hair cells of the mammalian is_associated_with::cochlea.

Gene
The human GIPC3 gene is located on the short arm of is_associated_with::chromosome 19 at p13.3. The locus extends over ≈8 kbp and contains the six coding is_associated_with::exons that give raise to an open reading frame of 639 is_associated_with::nucleotides encoding the GIPC3 protein of 312 is_associated_with::amino acids. A single PDZ domain is located at amino acid position 122-189. In the mouse, Gipc3 is located on is_associated_with::chromosome 10 at cytogenetic band qC1. The genomic region covers a distance of 5.5 kbp. The six coding exons encode a protein of 297 amino acids. The PDZ domain is located at amino acid position 107-174.

Genetics
In the mouse, a is_associated_with::missense mutation in Gipc3 (c.343G>A) leads to a non-synonymous amino acid replacement (p.G115R) in the loop connecting two beta strands of the PDZ domain. is_associated_with::Glycine 115 is conserved in all GIPC proteins. Missense (c.785C>T; p. L262R) and nonsense (c.903G>A, p.W301X) mutations in human GIPC3 cause congenital is_associated_with::sensorineural hearing impairment in families segregating non-syndromic is_associated_with::hearing loss DFNB15 and DFNB95.

Phenotypes
Mice of the is_associated_with::Black Swiss strain develop early-onset slowly progressing sensorineural hearing loss. A genetic study identified two is_associated_with::quantitative trait loci (QTL) that control hearing function. One QTL, named age-related hearing loss 5 (ahl5) localizes to chromosome 10 and accounted for ca. 60% of the variation in hearing thresholds. A second QTL, ahl6, localized to chromosome 18 and has a smaller effect size. Besides their hearing impairment, Black Swiss mice also are hypersensitive to acoustic stimulation, reacting with is_associated_with::seizures (audiogenic seizures) to loud is_associated_with::white noise. A genetic locus conferring susceptibility was identified (juvenile audiogenic monogenic seizures1, jams1) on chromosome 10. A positional cloning approach aimed to decipher the genetic basis of both the hearing loss and is_associated_with::audiogenic seizure susceptibility subsequently identified the is_associated_with::glycine to is_associated_with::arginine substitution in Gipc3 as the underlying cause.

In humans, individuals with the p.W301X missense mutation (DFNB95) exhibit bilateral sensorineural hearing loss with threshold shifts of 70-80 dB hearing levels as early as 11 months of age.

Interactions
The is_associated_with::PDZ domain of GIPC family proteins interact with:
 * Frizzled-3 (is_associated_with::FZD3) class of WNT receptor,
 * insulin-like growth factor-I receptor (IGF1R),
 * receptor tyrosine kinase TrkA,
 * TGF-beta type III receptor (TGF-beta RIII),
 * integrin alpha6A (is_associated_with::ITGA6),
 * transmembrane glycoprotein is_associated_with::TPBG, and
 * is_associated_with::RGS19/RGS-GAIP.