Rare KCNQ4 variants found in public databases underlie impaired channel activity that may contribute to hearing impairment
Rare KCNQ4 variants found in public databases underlie impaired channel activity that may contribute to hearing impairment
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DOI：
10.1038/s12276-019-0300-9
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发表时间：
2019-08-21
影响因子：
12.8
通讯作者：
Gee, Heon Yung
中科院分区：
文献类型：
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作者：
Jung, Jinsei;Lin, Haiyue;Gee, Heon Yung
KCNQ4在常染色体显性非综合征性听力损失（NSHL）中经常发生突变，NSHL是一种典型的迟发性，初始高频损失，随时间推移而进展（DFNA 2）。大多数与听力损失相关的KCNQ4突变聚集在蛋白质的孔区域周围，并导致KCNQ4介导的钾电流丧失。为了了解KCNQ4变体对NSHL的贡献，我们调查了公共数据库，发现17个功能丧失和6个错义KCNQ4变体影响孔区域周围的氨基酸。错义变体尚未被报道为致病性的，并且在人群中以低频率（次要等位基因频率< 0.0005）存在。我们研究了这些变体的功能影响，有趣的是，这些变体诱导钾通道活性降低而不改变通道蛋白的表达或运输，在功能上与DFNA 2相关的KCNQ4突变相似。因此，这些变异可能是迟发性听力损失的危险因素，携带这些变异中的任何一种的个体可能在成年期发生听力损失。降低的通道活性可以通过KCNQ激活剂来挽救，这表明了医疗干预的可能性。这些发现表明，KCNQ4变异体可能比预期更有助于晚发型NSHL，因此，该基因的遗传筛查对于预防和治疗NSHL非常重要。
KCNQ4 is frequently mutated in autosomal dominant non-syndromic hearing loss (NSHL), a typically late-onset, initially high-frequency loss that progresses over time (DFNA2). Most KCNQ4 mutations linked to hearing loss are clustered around the pore region of the protein and lead to loss of KCNQ4-mediated potassium currents. To understand the contribution of KCNQ4 variants to NSHL, we surveyed public databases and found 17 loss-of-function and six missense KCNQ4 variants affecting amino acids around the pore region. The missense variants have not been reported as pathogenic and are present at a low frequency (minor allele frequency < 0.0005) in the population. We examined the functional impact of these variants, which, interestingly, induced a reduction in potassium channel activity without altering expression or trafficking of the channel protein, being functionally similar to DFNA2-associated KCNQ4 mutations. Therefore, these variants may be risk factors for late-onset hearing loss, and individuals harboring any one of these variants may develop hearing loss during adulthood. Reduced channel activity could be rescued by KCNQ activators, suggesting the possibility of medical intervention. These findings indicate that KCNQ4 variants may contribute more to late-onset NSHL than expected, and therefore, genetic screening for this gene is important for the prevention and treatment of NSHL.