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 (SLC26A5^W70X/R130S). Our recent study showed that mice homozygous for p.R130S (Slc26a5^R130S/R130S) suffer from hearing loss that is ascribed to significantly reduced motor kinetics of prestin. Given that W70X-prestin is nonfunctional, compound heterozygous Slc26a5^R130S/− mice were used as a model for human SLC26A5^W70X/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 prestin's motor action. Thus, this study defines the pathogenic roles of p.R130S prestin and identifies a limited time window for potential clinical intervention.

DFNB61 是一种隐性遗传性非综合征性听力损失，由SLC26A5突变引起，SLC26A5 是编码电压驱动运动蛋白 prestin 的基因。Prestin 在介导耳蜗放大的听觉外毛细胞中大量表达。在这些无义和错义变化的复合杂合患者中鉴定出两个 DFNB61 相关的SLC26A5变异，p.W70X 和 p.R130S ( SLC26A5 ^W70X/R130S )。我们最近的研究表明，p.R130S（Slc26a5 ^R130S/R130S）纯合子小鼠患有听力损失，这归因于 prestin 的运动动力学显着降低。鉴于 W70X-prestin 是无功能的，复合杂合Slc26a5 ^R130S/−小鼠被用作人类SLC26A5 ^W70X/R130S的模型。通过检查 p.R130S prestin 是 prestin 蛋白产生的唯一等位基因时的病理生理学后果，我们确定这种错义变化除了对 prestin 的运动作用产生影响外，还导致进行性外毛细胞丢失。因此，本研究定义了 p.R130S prestin 的致病作用，并确定了潜在临床干预的有限时间窗口。