Kamada Fumiaki, Kure Shigeo, Kudo Takayuki, Suzuki Yoichi, Oshima Takeshi, Ichinohe Akiko, Kojima Kanako, Niihori Tetsuya, Kanno Junko, Narumi Yoko, Narisawa Ayumi, Kato Kumi, Aoki Yoko, Ikeda Katsuhisa, Kobayashi Toshimitsu, Matsubara Yoichi
Department of Medical Genetics, Tohoku University School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai 980-8574, Japan.
21st COE Program "Comprehensive Research and Education Center for Planning of Drug Development and Clinical Evaluation", Tohoku University, Sendai, Japan.
J Hum Genet. 2006;51(5):455-460. doi: 10.1007/s10038-006-0384-7. Epub 2006 Apr 5.
Autosomal-dominant, nonsyndromic hearing impairment is clinically and genetically heterogeneous. 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.
常染色体显性非综合征性听力障碍在临床和遗传上具有异质性。我们遇到了一个大型日本家系，其中非综合征性听力损失以常染色体显性方式遗传。全基因组连锁研究表明与1号染色体p34上的DFNA2位点连锁。对编码钾通道的KCNQ4进行突变分析，发现外显子1中有一个新的单碱基缺失，即c.211delC，它产生了一个没有跨膜结构域的严重截短蛋白（p.Q71fsX138）。此前，已报道KCNQ4中有六个错义突变和一个13碱基缺失，即c.211_223del。与携带211_223del突变的患者相比，携带KCNQ4错义突变的患者发病年龄更小，听力损失更严重。在我们目前的研究中，12名携带c.211delC突变的个体表现为迟发性和单纯高频听力损失。我们的结果支持基因型与表型的相关性，即与错义突变相比，KCNQ4缺失与迟发性和较轻的听力障碍相关。表型差异可能是由致病机制的差异引起的：缺失导致的单倍体不足和错义突变导致的显性负效应。
