A mouse model for nonsyndromic deafness (DFNB12) links hearing loss to defects in tip links of mechanosensory hair cells
A mouse model for nonsyndromic deafness (DFNB12) links hearing loss to defects in tip links of mechanosensory hair cells
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DOI：
10.1073/pnas.0900691106
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发表时间：
2009-03-31
影响因子：
11.1
通讯作者：
Mueller, Ulrich
中科院分区：
文献类型：
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作者：
Schwander, Martin;Xiong, Wei;Mueller, Ulrich
耳聋是人类最常见的感觉障碍形式，通常由单基因突变引起。有趣的是，一个基因的不同突变可以导致综合征和非综合征形式的耳聋，以及进行性和年龄相关的听力损失。我们在这里提供了一个解释与钙粘蛋白23基因（CDH 23）突变相关的表型变异。CDH 23无效等位基因导致视盲（Usher综合征1D型; USH 1D），而错义突变导致非综合征性耳聋（DFNB 12）。在正向遗传筛选中，我们已经鉴定了salsa小鼠，其由于Cdh 23错义突变建模DFNB 12而患有听力损失。与携带模拟USH 1D的CDH 23无效等位基因的waltzer小鼠相反，salsa小鼠的毛细胞发育不受影响。相反，被认为是毛细胞中的门控机械转导通道的尖端链接逐渐丢失。我们的研究结果表明，DFNB 12属于一类新的疾病，这是由尖端链接的缺陷。我们认为，其他基因突变导致USH 1和非综合征性耳聋也可能对毛细胞的发育和功能有不同的影响。
Deafness is the most common form of sensory impairment in humans and is frequently caused by single gene mutations. Interestingly, different mutations in a gene can cause syndromic and nonsyndromic forms of deafness, as well as progressive and age-related hearing loss. We provide here an explanation for the phenotypic variability associated with mutations in the cadherin 23 gene (CDH23). CDH23 null alleles cause deaf-blindness (Usher syndrome type 1D; USH1D), whereas missense mutations cause nonsyndromic deafness (DFNB12). In a forward genetic screen, we have identified salsa mice, which suffer from hearing loss due to a Cdh23 missense mutation modeling DFNB12. In contrast to waltzer mice, which carry a CDH23 null allele mimicking USH1D, hair cell development is unaffected in salsa mice. Instead, tip links, which are thought to gate mechanotransduction channels in hair cells, are progressively lost. Our findings suggest that DFNB12 belongs to a new class of disorder that is caused by defects in tip links. We propose that mutations in other genes that cause USH1 and nonsyndromic deafness may also have distinct effects on hair cell development and function.