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bioRxiv · 10.1101/2023.08.21.554157

The pathogenic roles of the p.R130S prestin variant in DFNB61 hearing loss

Takahashi, S.·Zhou, Y.·Cheatham, M. A.·Homma, K.
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Abstract

DFNB61 is a recessively inherited nonsyndromic hearing loss caused by mutations in SLC26A5, the gene that encodes the voltage-driven motor protein, prestin. Prestin is abundantly expressed in the auditory outer hair cells that mediate cochlear amplification. Two DFNB61-associated SLC26A5 variants, p.W70X and p.R130S, were identified in patients who are compound heterozygous for these nonsense and missense changes (SLC26A5W70X/R130S). Our recent study showed that mice homozygous for p.R130S (Slc26a5R130S/R130S) suffer from hearing loss that is ascribed to significantly reduced motor kinetics of prestin. Given that W70X-prestin is nonfunctional, compound heterozygous Slc26a5R130S/- mice were used as a model for human SLC26A5W70X/R130S. By examining the pathophysiological consequences of p.R130S prestin when it is the sole allele for prestin protein production, we determined that this missense change results in progressive outer hair cell loss in addition to its effects on prestins motor action. Thus, this study fully defines the pathogenic roles for the p.R130S prestin, which points to the presence of a limited time window for potential clinical intervention.

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Takahashi, S., Zhou, Y., Cheatham, M. A., Homma, K.. 2023-08-22. The pathogenic roles of the p.R130S prestin variant in DFNB61 hearing loss. https://doi.org/10.1101/2023.08.21.554157

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