Lack of PDZD7 long isoform disrupts ankle-link complex and causes hearing loss in mice.
Lack of PDZD7 long isoform disrupts ankle-link complex and causes hearing loss in mice.
复制标题
缺乏 PDZD7 长亚型会破坏踝关节复合体并导致小鼠听力损失
DOI：
10.1096/fj.201901657rr
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发表时间：
2020-01
期刊：
影响因子：
--
通讯作者：
Xu Z
中科院分区：
文献类型：
--
作者：
Du H;Zou L;Ren R;Li N;Li J;Wang Y;Sun J;Yang J;Xiong W;Xu Z
Usher综合征（USH）是遗传性耳聋-失明的最常见形式，以听力损失和视网膜色素变性为特征，伴有或不伴有前庭功能障碍。PDZD7是一种含有PDZ结构域的支架蛋白，被认为是USH修饰剂和遗传性USH的贡献者。在内耳毛细胞中，PDZD7定位于立体纤毛的踝关节区域，并与另外三种USH蛋白usher、WHRN和ADGRV1一起构成所谓的踝关节连接复合物。PDZD7基因经过选择性剪接，产生了两种类型的PDZD7亚型，即长亚型和短亚型。目前，我们还不知道是哪一种特定的异构体参与了踝环的形成和立体纤毛的发育。在这项工作中，我们发现PDZD7长异构体，而不是短异构体，定位于立体纤毛的踝关节区域。此外，我们通过在Pdzd7基因的外显子14上引入缺失，建立了Pdzd7突变小鼠，这可能导致长异构体的过早翻译停止，但短异构体不受影响。我们发现PDZD7长异构体的缺乏影响了其他踝关节环复杂成分在立体纤毛中的定位。因此，Pdzd7突变小鼠表现出立体纤毛发育缺陷和听力损失以及机械转导（MET）电流减少，这表明Pdzd7长异构体是毛细胞不可或缺的。此外，通过酵母双杂交筛选，我们确定了PDZD7长异构体特异性结合伙伴PIP5K1C，该伙伴已被证明在听力中发挥重要作用，并可能参与PDZD7的功能和/或运输。
Usher syndrome (USH) is the most frequent form of combined hereditary deafness-blindness, characterized by hearing loss and retinitis pigmentosa, with or without vestibular dysfunction. PDZD7 is a PDZ domain-containing scaffold protein that was suggested to be a USH modifier and a contributor to digenic USH. In the inner ear hair cells, PDZD7 localizes at the ankle region of the stereocilia and constitutes the so-called ankle-link complex together with three other USH proteins Usherin, WHRN, and ADGRV1. PDZD7 gene is subjected to alternative splicing, which gives rise to two types of PDZD7 isoforms, namely the long and short isoforms. At present, little is known which specific isoform is involved in ankle-link formation and stereocilia development. In this work, we showed that PDZD7 long isoform, but not short isoforms, localizes at the ankle region of the stereocilia. Moreover, we established Pdzd7 mutant mice by introducing deletions into exon 14 of the Pdzd7 gene, which causes potential premature translational stop in the long isoform but leaves short isoforms unaffected. We found that lack of PDZD7 long isoform affects the localization of other ankle-link complex components in the stereocilia. Consequently, Pdzd7 mutant mice showed stereocilia development deficits and hearing loss as well as reduced mechanotransduction (MET) currents, suggesting that PDZD7 long isoform is indispensable for hair cells. Furthermore, by performing yeast two-hybrid screening, we identified a PDZD7 long isoform-specific binding partner PIP5K1C, which has been shown to play important roles in hearing and might participate in the function and/or transportation of PDZD7.