Deficiency of Klc2 Induces Low-Frequency Sensorineural Hearing Loss in C57BL/6 J Mice and Human
Deficiency of Klc2 Induces Low-Frequency Sensorineural Hearing Loss in C57BL/6 J Mice and Human
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DOI：
10.1007/s12035-021-02422-w
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发表时间：
2021-05-20
影响因子：
5.1
通讯作者：
Chai, Renjie
中科院分区：
文献类型：
--
作者：
Fu, Xiaolong;An, Yachun;Chai, Renjie
耳蜗毛细胞（HCs）的运输系统对其功能至关重要，激酶蛋白家族通过细胞质中的微管网络运输许多细胞货物。在这里，我们发现Klc2（激酶蛋白轻链2），激酶蛋白1的轻链，介导货物结合和调节激酶蛋白1的运动，对耳蜗功能至关重要。我们产生了缺乏Klc2的小鼠，它们早在1个月大的时候就出现了低频听力丧失。我们证明，Klc2缺失导致线粒体转运异常和GABAA受体家族下调。此外，患者的全基因组测序（WGS）显示，KLC2与人类低频听力有关。因此，为了探索治疗方法，我们开发了含有Klc2宽型cDNA序列的腺相关病毒，并且Klc2缺失小鼠的病毒表现出明显的恢复，包括ABR阈值降低和毛细胞（OHC）损失减少。总之，我们表明运动蛋白转运系统在小鼠和人类耳蜗HC功能中起着不可或缺的特殊作用，线粒体定位对HC的存活至关重要。
The transport system in cochlear hair cells (HCs) is important for their function, and the kinesin family of proteins transports numerous cellular cargos via the microtubule network in the cytoplasm. Here, we found that Klc2 (kinesin light chain 2), the light chain of kinesin-1 that mediates cargo binding and regulates kinesin-1 motility, is essential for cochlear function. We generated mice lacking Klc2, and they suffered from low-frequency hearing loss as early as 1 month of age. We demonstrated that deficiency of Klc2 resulted in abnormal transport of mitochondria and the down-regulation of the GABAA receptor family. In addition, whole-genome sequencing (WGS) of patient showed that KLC2 was related to low-frequency hearing in human. Hence, to explore therapeutic approaches, we developed adeno-associated virus containing the Klc2 wide-type cDNA sequence, and Klc2-null mice delivered virus showed apparent recovery, including decreased ABR threshold and reduced out hair cell (OHC) loss. In summary, we show that the kinesin transport system plays an indispensable and special role in cochlear HC function in mice and human and that mitochondrial localization is essential for HC survival.