A frameshift mutation in GRXCR2 causes recessively inherited hearing loss.
A frameshift mutation in GRXCR2 causes recessively inherited hearing loss.
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DOI：
10.1002/humu.22545
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发表时间：
2014-05
期刊：
影响因子：
3.9
通讯作者：
Naz, Sadaf
中科院分区：
文献类型：
--
作者：
Imtiaz, Ayesha;Kohrman, David C.;Naz, Sadaf
超过3.6亿人在生命的早期或晚期受到一定程度的听力损失的影响。这种疾病的遗传原因存在于大多数病例中。我们将人类听力损失的基因座（DFNB101）定位在一个巴基斯坦血缘家庭的染色体5q上。外显子组测序显示GRXCR2中的插入突变是该家族受影响个体中中度至重度和可能进行性听力损失的原因。预计移码突变会影响GRXCR 2的保守的富含半胱氨酸的区域，并导致C末端的异常延伸。通过细胞转染的功能研究表明，突变蛋白相对于野生型GRXCR2是不稳定的和错误定位的，与功能缺失突变一致。同时报告了Grxcr2的靶向破坏导致小鼠听力损失。该动物模型中的结构异常表明GRXCR 2在静纤毛束的发育中的作用，静纤毛束是耳蜗感觉细胞顶面上的专门结构，对于声音检测至关重要。我们的研究结果表明，GRXCR2应考虑在早期发病，中度至重度和进行性听力损失的个体的差异遗传诊断。
More than 360 million humans are affected with some degree of hearing loss, either early or later in life. A genetic cause for the disorder is present in a majority of the cases. We mapped a locus (DFNB101) for hearing loss in humans to chromosome 5q in a consanguineous Pakistani family. Exome sequencing revealed an insertion mutation in GRXCR2 as the cause of moderate to severe and likely progressive hearing loss in the affected individuals of the family. The frameshift mutation is predicted to affect a conserved, cysteine-rich region of GRXCR2, and to result in an abnormal extension of the C-terminus. Functional studies by cell transfections demonstrated that the mutant protein is unstable and mislocalized relative to wild type GRXCR2, consistent with a loss of function mutation. Targeted disruption of Grxcr2 is concurrently reported to cause hearing loss in mice. The structural abnormalities in this animal model suggest a role for GRXCR2 in the development of stereocilia bundles, specialized structures on the apical surface of sensory cells in the cochlea that are critical for sound detection. Our results indicate that GRXCR2 should be considered in differential genetic diagnosis for individuals with early onset, moderate to severe and progressive hearing loss.
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