Prestin, a cochlear motor protein, is defective in non-syndromic hearing loss

Abstract

Prestin, a membrane protein that is highly and almost exclusively expressed in the outer hair cells (OHCs) of the cochlea, is a motor protein which senses membrane potential and drives rapid length changes in OHCs. Surprisingly, prestin is a member of a gene family, solute carrier (SLC) family 26, that encodes anion transporters and related proteins. Of nine known human genes in this family, three (SLC26A2, SLC26A3 and SLC26A4) are associated with different human hereditary diseases. The restricted expression of prestin in OHCs, and its proposed function as a mechanical amplifier, make it a strong candidate gene for human deafness. Here we report the cloning and characterization of four splicing isoforms for the human prestin gene (SLC26A5a, b, c and d). SLC26A5a is the predominant form of prestin whereas the others showed limited distribution associated with certain developmental stages. Based on the functional importance of prestin we screened for possible mutations involving the prestin gene in a group of deaf probands. We have identified a 5'-UTR splice acceptor mutation (IVS2-2A>G) in exon 3 of the prestin gene, which is responsible for recessive non-syndromic deafness in two unrelated families. In addition, a high frequency of heterozygosity for the same mutation was observed in these subjects, suggesting the possibility of semi-dominant influence of the mutation in causing hearing loss. Finally, the observation of this mutation only in the Caucasian probands indicated an association with a specific ethnic background. This study thereby reveals an essential function of prestin in human auditory processing.

Overexpression of X-linked inhibitor of apoptosis protein protects against noise-induced hearing loss in mice

“…3,4,63,64 Another possibility is damage to the lateral walls of the OHCs, especially structures related to the function of prestin, 5,61,62,65,66 the motor protein critical for the function of OHCs as a mechanical amplifier. [67][68][69][70] The acoustic overstimulation used in this experiment was intense and produced a widespread threshold shift, although larger threshold shifts were seen above 4 kHz. At the lowest frequency tested (2 kHz), the threshold shifts in both groups were small.…”

Improving hearing loss gene testing: a systematic review of gene evidence toward more efficient next-generation sequencing–based diagnostic testing and interpretation

“…The gene-disease association for SLC26A5 was suggested in a study by Liu et al, 30 in which a homozygous 5′-untranslated region splice acceptor variant in exon 3 of this gene was identified in two families with presumed recessive nonsyndromic deafness (a sibling pair in one family and a singleton in the second family). Although this variant is predicted to disrupt splicing, there are no functional data to support the prediction and limited data on the impact of the absence of the 5′-untranslated region on gene expression.…”

Expression of ion transport-associated proteins in human efferent and epididymal ducts

“…During passage through the epididymal ducts, the composition of the luminal fluid is further gradually changed by sequential absorption and secretion processes (Turner 2002, Wong et al 2002. Water absorption in efferent ducts is allowed by interdependent transport of Cl K and Na C , which may be mediated by an apical anion Cl hereditary diseases when mutated (Hastbacka et al 1994, Hoglund et al 1996, Everett et al 1997, Toure et al 2001, Liu et al 2003 OMIM database which can be viewed online at www. ncbi.nlm.nih.gov/entrez/query.fcgi?db=OMIM).…”