# GIPC3
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{{Short description|Protein-coding gene in the species Homo sapiens}}
{{Infobox_gene}}
'''PDZ domain-containing protein GIPC3''' is a [protein](/source/protein) that in humans is encoded by the ''GIPC3'' [gene](/source/gene).[{{cite web | title = Entrez Gene: GIPC PDZ domain containing family| url = https://www.ncbi.nlm.nih.gov/gene?Db=gene&Cmd=ShowDetailView&TermToSearch=126326}}][{{cite journal |vauthors=Saitoh T, Mine T, Katoh M | title = Molecular cloning and characterization of human GIPC3, a novel gene homologous to human GIPC1 and GIPC2 | journal = Int. J. Oncol. | volume = 20 | issue = 3 | pages = 577–82 |date=March 2002 | pmid = 11836571 | doi = 10.3892/ijo.20.3.577}}] GIPC3 is a member of the GIPC (GAIP-interacting protein C terminus) gene family that also includes [GIPC1](/source/GIPC1) and [GIPC2](/source/GIPC2).[{{cite journal | author = Katoh M | title = GIPC gene family (Review) | journal = Int. J. Mol. Med. | volume = 9 | issue = 6 | pages = 585–9 |date=June 2002 | pmid = 12011974 | doi = 10.3892/ijmm.9.6.585}}] The encoded protein, GIPC3, features a centrally located [PDZ domain](/source/PDZ_domain), which is flanked on each side by a single GIPC-homology domain.[{{Cite journal
| last1 = Katoh | first1 = M.
| title = GIPC gene family (Review)
| journal = International Journal of Molecular Medicine
| volume = 9
| issue = 6
| pages = 585–589
| year = 2002
| pmid = 12011974
| doi=10.3892/ijmm.9.6.585
}}]
==Function==
GIPC3 is thought to be important for acoustic signal acquisition and propagation in [hair cells](/source/hair_cells) of the mammalian [cochlea](/source/cochlea).
==Gene==
The human ''GIPC3'' gene is located on the short arm of [chromosome 19](/source/chromosome_19) at p13.3. The locus extends over about 8 kbp and contains the six coding [exon](/source/exon)s that give rise to an [open reading frame](/source/open_reading_frame) of 639 [nucleotide](/source/nucleotide)s encoding the GIPC3 protein of 312 [amino acid](/source/amino_acid)s. A single PDZ domain is located at amino acid position 122-189.
In the mouse, ''Gipc3'' is located on [chromosome 10](/source/chromosome_10) at [cytogenetic band](/source/Cytogenetics) qC1. The [genomic](/source/genome) 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 [missense mutation](/source/missense_mutation) in ''Gipc3'' (c.343G>A) leads to a non-synonymous [amino acid replacement](/source/amino_acid_replacement) (p.G115R) in the loop connecting two beta strands of the PDZ domain. [Glycine](/source/Glycine) 115 is conserved in all GIPC proteins.[{{cite journal |vauthors=Charizopoulou N, Lelli A, Schraders M, Ray K, Hildebrand MS, Ramesh A, Srisailapathy CR, Oostrik J, Admiraal RJ, Neely HR, Latoche JR, Smith RJ, Northup JK, Kremer H, Holt JR, Noben-Trauth K | title = Gipc3 mutations associated with audiogenic seizures and sensorineural hearing loss in mouse and human | journal = Nat Commun | volume = 2 | issue = 2| article-number = 201 |date=February 2011 | pmid = 21326233 | doi = 10.1038/ncomms1200 | pmc=3105340| bibcode = 2011NatCo...2..201C }}]
Missense (c.785C>T; p. L262R) and [nonsense](/source/Nonsense_mutation) (c.903G>A, p.W301X) mutations in human GIPC3 cause congenital [sensorineural hearing impairment](/source/sensorineural_hearing_impairment) in families segregating non-syndromic [hearing loss](/source/hearing_loss) DFNB15 and DFNB95.
==Phenotypes==
Mice of the [Black Swiss](/source/Black_Swiss) strain develop early-onset slowly progressing sensorineural hearing loss. A genetic study identified two [quantitative trait loci](/source/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.[{{Cite journal
| last1 = Drayton | first1 = M.
| last2 = Noben-Trauth | first2 = K.
| title = Mapping quantitative trait loci for hearing loss in Black Swiss mice
| journal = Hearing Research
| volume = 212
| issue = 1–2
| pages = 128–139
| year = 2006
| pmid = 16426780
| doi = 10.1016/j.heares.2005.11.006
| s2cid = 23928550
| url = https://zenodo.org/record/1259003
}}] Besides their hearing impairment, Black Swiss mice also are hypersensitive to acoustic stimulation, reacting with [seizures](/source/seizures) (audiogenic seizures) to loud [white noise](/source/white_noise).[{{Cite journal
| last1 = Misawa | first1 = H.
| last2 = Sherr | first2 = E. H.
| last3 = Lee | first3 = D. J.
| last4 = Chetkovich | first4 = D. M.
| last5 = Tan | first5 = A.
| last6 = Schreiner | first6 = C. E.
| last7 = Bredt | first7 = D. S.
| title = Identification of a monogenic locus (jams1) causing juvenile audiogenic seizures in mice
| journal = Journal of Neuroscience
| volume = 22
| issue = 23
| pages = 10088–10093
| year = 2002
| pmid = 12451109
| doi = 10.1523/JNEUROSCI.22-23-10088.2002
| pmc = 6758732
| doi-access = free
}}] A genetic locus conferring susceptibility was identified (juvenile audiogenic monogenic seizures1, ''jams1'') on chromosome 10. A [positional cloning approach](/source/positional_cloning) aimed to decipher the genetic basis of both the hearing loss and [audiogenic seizure susceptibility](/source/audiogenic_seizure_susceptibility) subsequently identified the [glycine](/source/glycine) to [arginine](/source/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 [PDZ domain](/source/PDZ_domain) of GIPC family proteins interact with: