The pathogenic roles of the p.R130S prestin variant in DFNB61 hearing loss.
The pathogenic roles of the p.R130S prestin variant in DFNB61 hearing loss.
复制标题
p.R130S prestin 变体在 DFNB61 听力损失中的致病作用。
DOI：
10.1101/2023.08.21.554157
复制
发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Homma,Kazuaki
中科院分区：
文献类型：
--
作者：
Takahashi,Satoe;Zhou,Yingjie;Cheatham,MaryAnn;Homma,Kazuaki
dfnb61是一种隐性遗传的非综合征性听力损失，由slc26a5基因突变引起，该基因编码电压驱动的马达蛋白prestin。Prestin在介导耳蜗放大的听觉外毛细胞中大量表达。两个DFNB61相关的slc26a5变异，p.W70X和p.R130S，在这些无义和错义变化（SLC26A5W70X/R130S）的复合杂合患者中被鉴定出来。我们最近的研究表明，p.R130S纯合子（Slc26a5R130S/R130S）小鼠的听力损失归因于prestin的运动动力学显著降低。考虑到W70X‐prestin是无功能的，我们使用复合杂合体slc26a5r130s /−小鼠作为人类slc26a5w70x /R130S的模型。当p.R130S prestin是prestin蛋白产生的唯一等位基因时，通过检查其病理生理后果，我们确定这种错义改变除了影响prestin的运动作用外，还会导致进行性外毛细胞损失。因此，本研究明确了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。电压驱动马达蛋白prestin由yslc26a5编码，在耳蜗外毛细胞（OHCs）中大量表达。普司汀对缺乏普司汀的小鼠正常听力的重要性得到证实；然而，迄今为止在人类患者中发现的特异性slc26a5变异均未被实验证明具有致病性。在这项研究中，我们使用细胞系和小鼠模型来确定在中度至重度听力损失患者中发现的复合杂合p.W70X （c.209G> a）和p.R130S (c.390A>C) slc26a5变异的致病作用。与患者一样，携带p.R130SSlc26a5拷贝的小鼠表现出OHC功能障碍和进行性变性，从而导致先天性进行性听力损失。这是第一个功能性研究，报告了slc26a5变异的致病性，并指出在受影响的OHCs丢失之前，存在潜在的临床干预治疗时间窗口。
AbstractDFNB61 is a recessively inherited nonsyndromic hearing loss caused by mutations inSLC26A5, 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‐associatedSLC26A5variants, 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 heterozygousSlc26a5R130S/−mice were used as a model for humanSLC26A5W70X/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 pointsThe voltage‐driven motor protein, prestin, is encoded bySLC26A5and 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 specificSLC26A5variants 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)SLC26A5variants identified in patients with moderate to profound hearing loss.As in patients, mice carrying one copy of p.R130SSlc26a5 showed OHC dysfunction and progressive degeneration, which results in congenital progressive hearing loss.This is the first functional study reporting pathogenicSLC26A5variants and pointing to the presence of a therapeutic time window for potential clinical interventions targeting the affected OHCs before they are lost.