Abstract
BackgroundPrestin, encoded by the gene SLC26A5, is a transmembrane protein of the cochlear outer hair cell (OHC). Prestin is required for the somatic electromotile activity of OHCs, which is absent in OHCs and causes severe hearing impairment in mice lacking prestin. In humans, the role of sequence variations in SLC26A5 in hearing loss is less clear. Although prestin is expected to be required for functional human OHCs, the clinical significance of reported putative mutant alleles in humans is uncertain.Methodology/Principal FindingsTo explore the hypothesis that SLC26A5 may act as a modifier gene, affecting the severity of hearing loss caused by an independent etiology, a patient-control cohort was screened for DNA sequence variations in SLC26A5 using sequencing and allele specific methods. Patients in this study carried known pathogenic or controversial sequence variations in GJB2, encoding Connexin 26, or confirmed or suspected sequence variations in SLC26A5; controls included four ethnic populations. Twenty-three different DNA sequence variations in SLC26A5, 14 of which are novel, were observed: 4 novel sequence variations were found exclusively among patients; 7 novel sequence variations were found exclusively among controls; and, 12 sequence variations, 3 of which are novel, were found in both patients and controls. Twenty-one of the 23 DNA sequence variations were located in non-coding regions of SLC26A5. Two coding sequence variations, both novel, were observed only in patients and predict a silent change, p.S434S, and an amino acid substitution, p.I663V. In silico analysis of the p.I663V amino acid variation suggested this variant might be benign. Using Fisher's exact test, no statistically significant difference was observed between patients and controls in the frequency of the identified DNA sequence variations. Haplotype analysis using HaploView 4.0 software revealed the same predominant haplotype in patients and controls and derived haplotype blocks in the patient-control cohort similar to those generated from the International HapMap Project.Conclusions/SignificanceAlthough these data fail to support a hypothesis that SLC26A5 acts as a modifier gene of GJB2-related hearing loss, the sample size is small and investigation of a larger population might be more informative. The 14 novel DNA sequence variations in SLC26A5 reported here will serve as useful research tools for future studies of prestin.
Highlights
The human ear is capable of perceiving sounds from 20– 20,000 Hz and can distinguish a difference of as little as 0.2–0.5% [1,2]
Stereocilia, which sit atop the outer hair cells (OHCs), embed within the tectorial membrane (TM) and are deflected with the passage of sound pressure waves, triggering mechanotransducer ion channels to open and close, allowing the cell to depolarize and hyperpolarize, respectively
Fourteen of the DNA sequence variations identified among patients, 13 single nucleotide substitutions and the 1 small deletion, were found in introns, while 2 single nucleotide substitutions were found in the coding region of SLC26A5 including g.56167A.G which predicts a synonymous change p.S434S and g.69743A.G which predicts the amino acid substitution p.I663V (Table 1, Table 2)
Summary
The human ear is capable of perceiving sounds from 20– 20,000 Hz and can distinguish a difference of as little as 0.2–0.5% [1,2]. Stereocilia, which sit atop the outer hair cells (OHCs), embed within the TM and are deflected with the passage of sound pressure waves, triggering mechanotransducer ion channels to open and close, allowing the cell to depolarize and hyperpolarize, respectively. These changes in OHC membrane potential are converted into mechanical forces, causing the cell to rapidly lengthen and shorten, and in turn, move the basilar membrane, to result in a hundred-fold amplification of sound and a vastly improved ability to discriminate frequencies. Prestin, encoded by the gene SLC26A5, is a transmembrane protein of the cochlear outer hair cell (OHC). Prestin is expected to be required for functional human OHCs, the clinical significance of reported putative mutant alleles in humans is uncertain
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