Chen Jianfu, Yang Li, Yang Aifen, Zhu Yi, Zhao Jianyue, Sun Dongmei, Tao Zhihua, Tang Xiaowen, Wang Jindan, Wang Xinjian, Tsushima Asami, Lan Jinshan, Li Weixing, Wu Fangli, Yuan Qian, Ji Jingzhang, Feng Jinbao, Wu Chunli, Liao Zhisu, Li Zhiyuan, Greinwald John H, Lu Jianxin, Guan Min-Xin
Department of Otolaryngology, the First Affiliated Hospital, Wenzhou Medical College, Wenzhou, Zhejiang, China.
Gene. 2007 Oct 15;401(1-2):4-11. doi: 10.1016/j.gene.2007.06.009. Epub 2007 Jun 20.
We report here the clinical, genetic and molecular characterization of three Han Chinese pedigrees with maternally transmitted aminoglycoside-induced and nonsyndromic bilateral hearing loss. Clinical evaluation revealed the wide range of severity, age-at-onset and audiometric configuration of hearing impairment in matrilineal relatives in these families. The penetrances of hearing loss in these pedigrees were 28%, 20%, and 15%, with an average of 21%, when aminoglycoside-induced deafness was included. When the effect of aminoglycosides was excluded, the penetrances of hearing loss in these seven pedigrees were 21%, 13% and 8%, with an average of 14%. Sequence analysis of the complete mitochondrial genomes in these pedigrees showed the presence of the deafness-associated 12S rRNA C1494T mutation, in addition to distinct sets of mtDNA polymorphism belonging to Eastern Asian haplogroups F1a1, F1a1 and D5a2, respectively. This suggested that the C1494T mutation occurred sporadically and multiplied through evolution of the mtDNA. The absence of functionally significant mutations in tRNA and rRNAs or secondary LHON mutations in their mtDNA suggests that these mtDNA haplogroup-specific variants may not play an important role in the phenotypic expression of the C1494T mutation in those Chinese families. In addition, the lack of significant mutation in the GJB2 gene ruled out the possible involvement of GJB2 in the phenotypic expression of the C1494T mutation in those affected subjects. However, aminoglycosides and other nuclear modifier genes play a modifying role in the phenotypic manifestation of the C1494T mutation in these Chinese families.
我们在此报告三个母系遗传的氨基糖苷类药物所致非综合征性双侧听力损失的汉族家系的临床、遗传和分子特征。临床评估显示，这些家系中母系亲属的听力障碍严重程度、发病年龄和听力图类型范围广泛。当纳入氨基糖苷类药物所致耳聋时，这些家系中听力损失的外显率分别为28%、20%和15%，平均为21%。排除氨基糖苷类药物的影响后，这七个家系中听力损失的外显率分别为21%、13%和8%，平均为14%。对这些家系的完整线粒体基因组进行序列分析发现，除了分别属于东亚单倍群F1a1、F1a1和D5a2的不同线粒体DNA多态性集合外，还存在与耳聋相关的12S rRNA C1494T突变。这表明C1494T突变是散发性发生的，并通过线粒体DNA的进化而倍增。其线粒体DNA中tRNA和rRNA无功能显著突变或继发性Leber遗传性视神经病变（LHON）突变，提示这些线粒体DNA单倍群特异性变异可能在那些中国家系中C1494T突变的表型表达中不起重要作用。此外，GJB2基因无显著突变排除了GJB2在那些受影响个体中C1494T突变表型表达中的可能参与。然而，氨基糖苷类药物和其他核修饰基因在这些中国家系中C1494T突变的表型表现中起修饰作用。
