In vertebrates, 14-3-3 proteins form a family of seven highly conserved isoforms with chaperone activity, which bind phosphorylated substrates mostly involved in regulatory and checkpoint pathways. 14-3-3 proteins are the most abundant protein in the brain and are abundantly found in the cerebrospinal fluid in neurodegenerative diseases, suggesting a critical role in neuron physiology and death. Here we show that 14-3-3eta-deficient mice displayed auditory impairment accompanied by cochlear hair cells' degeneration. We show that 14-3-3eta is highly expressed in the outer and inner hair cells, spiral ganglion neurons of cochlea and retinal ganglion cells. Screening of YWHAH, the gene encoding the 14-3-3eta isoform, in non-syndromic and syndromic deafness, revealed seven non-synonymous variants never reported before. Among them, two were predicted to be damaging in families with syndromic deafness. In vitro, variants of YWHAH induce mild mitochondrial fragmentation and severe susceptibility to apoptosis, in agreement with a reduced capacity of mutated 14-3-3eta to bind the pro-apoptotic Bad protein. This study demonstrates that YWHAH variants can have a substantial effect on 14-3-3eta function and that 14-3-3eta could be a critical factor in the survival of outer hair cells.

中文翻译：

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Ywhah 在小鼠中的功能丧失会导致耳聋和耳蜗外毛细胞的退化。

在脊椎动物中，14-3-3 蛋白形成了一个由七种高度保守的具有伴侣活性的亚型组成的家族，它们结合主要参与调节和检查点途径的磷酸化底物。14-3-3 蛋白是大脑中最丰富的蛋白质，在神经退行性疾病的脑脊液中大量存在，表明在神经元生理和死亡中起关键作用。在这里，我们显示 14-3-3eta 缺陷小鼠表现出伴有耳蜗毛细胞退化的听觉障碍。我们发现 14-3-3eta 在外毛细胞和内毛细胞、耳蜗螺旋神经节神经元和视网膜神经节细胞中高度表达。YWHAH（编码 14-3-3eta 同种型的基因）在非综合征性和综合征性耳聋中的筛选揭示了七个以前从未报道过的非同义变体。其中，预计有两个对患有综合征性耳聋的家庭造成损害。在体外，YWHAH 的变体诱导轻度线粒体断裂和对细胞凋亡的严重易感性，这与突变的 14-3-3eta 结合促凋亡 Bad 蛋白的能力降低一致。这项研究表明，YWHAH 变体可以对 14-3-3eta 功能产生重大影响，并且 14-3-3eta 可能是外毛细胞存活的关键因素。