Cingulin (CGN) is a cytoskeleton-associated protein localized at the apical junctions of epithelial cells. CGN interacts with major cytoskeletal filaments and regulates RhoA activity. However, physiological roles of CGN in development and human diseases are currently unknown. Here, we report a multi-generation family presenting with autosomal dominant non-syndromic hearing loss (ADNSHL) that co-segregates with a CGN heterozygous truncating variant, c.3330delG (p.Leu1110Leufs*17). CGN is normally expressed at the apical cell junctions of the organ of Corti, with enriched localization at hair cell cuticular plates and circumferential belts. In mice, the putative disease-causing mutation results in reduced expression and abnormal subcellular localization of the CGN protein, abolishes its actin polymerization activity, and impairs the normal morphology of hair cell cuticular plates and hair bundles. Hair cell-specific Cgn knockout leads to high-frequency hearing loss. Importantly, Cgn mutation knockin mice display noise-sensitive, progressive hearing loss and outer hair cell degeneration. In summary, we identify CGN c.3330delG as a pathogenic variant for ADNSHL and reveal essential roles of CGN in the maintenance of cochlear hair cell structures and auditory function.

中文翻译：

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Cingulin 调节毛细胞角质板形态，是人类和小鼠听力所必需的

Cingulin (CGN) 是一种位于上皮细胞顶端连接处的细胞骨架相关蛋白。CGN 与主要细胞骨架丝相互作用并调节 RhoA 活性。然而，CGN 在发育和人类疾病中的生理作用目前尚不清楚。在此，我们报告了一个患有常染色体显性非综合征性听力损失 (ADNSHL) 的多代家庭，该家族与CGN杂合截短变异 c.3330delG (p.Leu1110Leufs*17)共分离。CGN 通常在柯蒂氏器的顶端细胞连接处表达，在毛细胞角质板和圆周带处富集定位。在小鼠中，假定的致病突变导致 CGN 蛋白表达减少和异常亚细胞定位，消除其肌动蛋白聚合活性，并损害毛细胞角质板和毛束的正常形态。毛细胞特异性Cgn敲除会导致高频听力损失。重要的是，Cgn突变敲入小鼠表现出对噪音敏感、进行性听力损失和外毛细胞变性。总之，我们将CGN c.3330delG 确定为 ADNSHL 的致病性变异，并揭示了 CGN 在维持耳蜗毛细胞结构和听觉功能中的重要作用。