A novel KCNQ4 one-base deletion in a large pedigree with hearing loss:: implication for the genotype-phenotype correlation
A novel KCNQ4 one-base deletion in a large pedigree with hearing loss:: implication for the genotype-phenotype correlation
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DOI：
10.1007/s10038-006-0384-7
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发表时间：
2006-01-01
影响因子：
3.5
通讯作者：
Matsubara, Yoichi
中科院分区：
文献类型：
--
作者：
Kamada, Fumiaki;Kure, Shigeo;Matsubara, Yoichi
常染色体显性非综合征性听力损失在临床和遗传上具有异质性我们遇到一个日本大型家系，其中非综合征性听力损失以常染色体显性方式遗传。一项全基因组连锁研究表明与染色体1 p34上的DFNA 2位点连锁。KCNQ 4编码钾通道的突变分析揭示了一个新的一个碱基缺失的外显子1，c.211delC，这产生了一个深刻的截短的蛋白质没有跨膜结构域（p.Q71fsX138）。此前，在KCNQ 4中已报道了6个错义突变和1个13碱基缺失（c.211_223del）。KCNQ 4错义突变的患者比211_223del突变的患者有更早的发病和更严重的听力损失。在我们目前的研究中，12名携带c.211delC突变的个体表现出迟发性和纯高频听力损失。我们的研究结果支持基因型-表型相关性，即KCNQ 4缺失与迟发性和轻度听力损伤相关，而不是错义突变。表型差异可能是由致病机制的差异引起的：缺失的单倍不足和错义突变的显性负效应。
Autosomal-dominant, nonsyndromic hearing impairment is clinically and genetically heterogcneous We encountered a large Japanese pedigree in which nonsyndromic hearing loss was inherited in an autosomal-dominant fashion. A genome-wide linkage study indicated linkage to the DFNA2 locus on chromosome 1p34. Mutational analysis of KCNQ4 encoding a potassium channel revealed a novel one-base deletion in exon 1, c.211delC, which generated a profoundly truncated protein without transmembrane domains (p.Q71fsX138). Previously, six missense mutations and one 13-base deletion, c.211_223del, had been reported in KCNQ4. Patients with the KCNQ4 missense mutations had younger-onset and more profound hearing loss than patients with the 211_223del mutation. In our Current study, 12 individuals with the c.211delC mutation manifested late-onset and pure high-frequency hearing loss. Our results Support the genotype-phenotype correlation that the KCNQ4 deletions are associated with later-onset and milder hearing impairment than the missense Mutations. The phenotypic difference may be caused by the difference in pathogenic mechanisms: haploinsufficiency in deletions and dominant-negative effect in missense mutations.