Pathogenic effects of a novel mutation (c.664_681del) in KCNQ4 channels associated with auditory pathology
Pathogenic effects of a novel mutation (c.664_681del) in KCNQ4 channels associated with auditory pathology
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DOI：
10.1016/j.bbadis.2010.09.001
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发表时间：
2011-04-01
影响因子：
6.2
通讯作者：
Kim, Un-Kyung
中科院分区：
文献类型：
--
作者：
Baek, Jeong-In;Park, Hong-Joon;Kim, Un-Kyung
听力损失是一种常见的沟通障碍，由各种环境和遗传因素引起。遗传性听力损失是非常异质性的，并且大多数此类病例涉及听觉通路中的感音神经缺陷。目前已知有57个常染色体显性遗传非综合征性听力损失（DFNA）基因座，其中22个基因座的致病基因已被确定。在本研究中，我们进行了全基因组连锁分析，在韩国家庭分离常染色体显性听力损失。我们观察到染色体1p34上的连锁，在这个位点上，我们检测到一个新的突变，该突变由编码电压门控钾通道的KCNQ4基因外显子4中的18个核苷酸缺失组成。我们进行了一项功能性体外研究，以分析该突变（c.664_681 del）沿着先前描述的两种KCNQ 4突变p.W276 S和p.G285 C的影响。尽管c.664_681del突变位于细胞间环中，并且先前描述的两个突变p.W276S和p.G285C位于孔区域中，但是所有突变体均通过显性负效应抑制正常通道功能。我们的分析表明，细胞间环是作为一个潜在的致病影响KCNQ4通道功能的网站孔区域的显着。(C)2010 Elsevier B.V.保留所有权利。
Hearing loss is a common communication disorder caused by various environmental and genetic factors. Hereditary hearing loss is very heterogeneous, and most of such cases involve sensorineural defects in the auditory pathway. There are currently 57 known autosomal dominant non-syndromic hearing loss (DFNA) loci, and the causative genes have been identified at 22 of these loci. In the present study, we performed a genome-wide linkage analysis in a Korean family segregating autosomal dominant hearing loss. We observed linkage on chromosome 1p34, and at this locus, we detected a novel mutation consisting of an 18 nucleotide deletion in exon 4 of the KCNQ4 gene, which encodes a voltage-gated potassium channel. We carried out a functional in vitro study to analyze the effects of this mutation (c.664_681del) along with two previously described KCNQ4 mutations, p.W276S and p.G285C. Although the c.664_681del mutation is located in the intercellular loop and the two previously described mutations, p.W276S and p.G285C, are located in the pore region, all mutants inhibit normal channel function by a dominant negative effect. Our analysis indicates that the intercellular loop is as significant as the pore region as a potential site of pathogenic effects on KCNQ4 channel function. (C) 2010 Elsevier B.V. All rights reserved.