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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 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. KEY POINTS: The voltage-driven motor protein, prestin, is encoded by SLC26A5 and expressed abundantly in cochlear outer hair cells (OHCs). The importance of prestin for normal hearing was demonstrated in mice lacking prestin; however, none of the specific SLC26A5 variants identified to date in human patients has been experimentally demonstrated to be pathogenic. In this study we used both cell lines and a mouse model to define the pathogenic role of compound heterozygous p.W70X (c.209G>A) and p.R130S (c.390A>C) SLC26A5 variants identified in patients with moderate to profound hearing loss. As in patients, mice carrying one copy of p.R130S Slc26a5 showed OHC dysfunction and progressive degeneration, which results in congenital progressive hearing loss. This is the first functional study reporting pathogenic SLC26A5 variants and pointing to the presence of a therapeutic time window for potential clinical interventions targeting the affected OHCs before they are lost.
摘要：
DFNB61是由SLC26A5突变引起的隐性遗传性非综合征性听力损失，SLC26A5是编码电压驱动运动蛋白的基因，Prestin.Prestin在介导耳蜗扩增的听觉外毛细胞中大量表达。两个DFNB61相关的SLC26A5变体，p.W70X和p.R130S,在这些无义和错义变化的复合杂合患者中鉴定（SLC26A5W70X/R130S）。我们最近的研究表明，p.R130S纯合的小鼠（Slc26a5R130S/R130S）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Slc26a5R130S/-小鼠用作人SLC26A5W70X/R130S的模型。通过检查p.R130Sprestin的病理生理后果，当它是prestin蛋白生产的唯一等位基因时，我们确定，这种错觉的改变导致进行性外毛细胞损失，除了它对prestin的运动动作的影响。因此，本研究定义了p.R130Sprestin的致病作用,并确定了潜在临床干预的有限时间窗.关键点：电压驱动的运动蛋白，Prestin,由SLC26A5编码并在耳蜗外毛细胞(OHCs)中大量表达。在缺乏prestin的小鼠中证明了prestin对正常听力的重要性；然而，迄今为止，在人类患者中鉴定出的特定SLC26A5变体均未通过实验证明具有致病性。在这项研究中，我们使用了细胞系和小鼠模型来定义复合杂合p.W70X（c.209G>A）和p.R130S（c.390A>C）SLC26A5变体的致病作用。和病人一样，携带一份p.R130SSlc26a5的小鼠表现出OHC功能障碍和进行性变性，导致先天性进行性听力损失。这是第一个功能性研究报告致病性SLC26A5变体，并指出在丢失之前针对受影响的OHC的潜在临床干预措施的治疗时间窗的存在。
