Mice with altered KCNQ4 K+ channels implicate sensory outer hair cells in human progressive deafness
Mice with altered KCNQ4 K+ channels implicate sensory outer hair cells in human progressive deafness
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DOI：
10.1038/sj.emboj.7600951
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发表时间：
2006-02-08
期刊：
影响因子：
11.4
通讯作者：
Jentsch, TJ
中科院分区：
文献类型：
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作者：
Kharkovets, T;Dedek, K;Jentsch, TJ
KCNQ4是一种M型K+通道，表达于内耳的感觉毛细胞和中枢听觉通路。KCNQ4突变是人类DFNA2显性进行性听力损失的基础。我们现在产生了KCNQ4基因被破坏或携带显性负DFNA2突变的小鼠。虽然KCNQ4在前庭毛细胞中有较强的表达，但前庭功能正常。最初只有轻微的听觉功能受损。然后，在Kcnq4(-/-)小鼠中，它在几周内下降，在携带显性负等位基因的小鼠中，在几个月内下降。这种进行性听力损失与外毛细胞的选择性退化是平行的。KCNQ4阻断使OHC的I-K、I-n电流消失。随之而来的毛细胞的去极化损害了声音的放大。内毛细胞及其传入突触基本保持完好。这些细胞只有轻微的去极化，并显示出接近正常的突触前功能。我们的结论是，DFNA2的听力损失主要是由于慢性去极化导致的毛细胞缓慢退化所致。
KCNQ4 is an M-type K+ channel expressed in sensory hair cells of the inner ear and in the central auditory pathway. KCNQ4 mutations underlie human DFNA2 dominant progressive hearing loss. We now generated mice in which the KCNQ4 gene was disrupted or carried a dominant negative DFNA2 mutation. Although KCNQ4 is strongly expressed in vestibular hair cells, vestibular function appeared normal. Auditory function was only slightly impaired initially. It then declined over several weeks in Kcnq4(-/-) mice and over several months in mice carrying the dominant negative allele. This progressive hearing loss was paralleled by a selective degeneration of outer hair cells (OHCs). KCNQ4 disruption abolished the I-K,I- n current of OHCs. The ensuing depolarization of OHCs impaired sound amplification. Inner hair cells and their afferent synapses remained mostly intact. These cells were only slightly depolarized and showed near-normal presynaptic function. We conclude that the hearing loss in DFNA2 is predominantly caused by a slow degeneration of OHCs resulting from chronic depolarization.