五个母系遗传非综合征性耳聋和药物性耳聋的中国汉族家系

Maternally inherited aminoglycoside-induced and nonsyndromic hearing loss in five Han Chinese pedigrees

目的通过对母系遗传非综合征性耳聋家系临床和分子遗传学特征分析，进一步探讨线粒体12S rRNA基因对母系遗传药物性耳聋的影响。方法收集5个非综合征性耳聋患者家系，提取基因组DNA，然后进行线粒体DNA全序列和间隙连接蛋白β2（gap junction protein beta 2，GJB2）基因扩增并测序分析。结果5个家系内和家系间的母系成员在听力损失、发病年龄和听力曲线上存在较大差异。5个家系耳聋发生的外显率分别为17．6％、50．0％、66．7％、31．3％和23．1％，平均外显率是37．7％。线粒体全序列显示家系间存在已知的1555A〉G突变和不同的多态性位点，分别属于东亚人群D4b2b、B4c1bl、F3、C1、D5a单倍型。这5个家系没有携带已知的线粒体DNA继发突变，但发现了2个保守性较高的ND1 L89T和C03A200T突变。而且，GJB2基因上未发现与耳聋相关的突变。结论这5个母系遗传非综合征性耳聋家系中，线粒体DNA继发突变、GJB2基因可能没有影响1555A〉G的表型表达。然而，氨基糖甙类抗生素、线粒体DNA多态性及其他核修饰基因可能对这5个耳聋家系的表型表达起到修饰作用。

Objective To study the effect of the mitochondrial 12S rRNA mutations on aminoglycoside-induced and nonsyndromic hearing loss, to carry out the clinical and molecular characterization of five Han Chinese pedigrees with maternally transmitted aminoglycoside-induced and nonsyndromic hearing loss. Methods Five pedigrees of maternally transmitted aminoglycoside-induced and nonsyndromic hearing loss were collected, genomic DNA was extracted, and complete mitochondrial genomes and the gap junction protein, beta 2 （GJB2） gene were amplified and sequenced. Results Clinical evaluation revealed a wide range of severity, age-at-onset and audiometric configuration of hearing impairment in the matrilineal relatives in these families. The penetrance rates of hearing loss in these pedigrees were 17. 6%, 50. 0%, 66. 7%, 31. 3% and 23. 1%, with an average of 37. 7%, when aminoglycoside-induced deafness was included. Sequence analysis of the complete mitochondrial genomes in these pedigrees identified the known 1555A〉G mutation and distinct sets of mitochondrial DNA（mtDNA） polymorphisms belonging to Eastern Asian haplogroups D4b2b, B4c1bl, F3, C1 and D5a, respectively. Of these variants, ND1 L89T and C03 A200T mutations resided at the highly conservative regions. However, there were no functionally significant mutations in tRNAs and rRNAs or secondary known mutations. No hearing loss related GJB2 gene mutation was observed. Conclusion The lack of significant mutation in the ruled out the possible involvement of GJB2 in the phenotypic expression of the 1555A〉G mutation in those affected subjects. However, aminoglycosides, mtDNA variations and other nuclear modifier genes may play an important role in the phenotypic manifestation of the 1555A〉G mutation in these Chinese families.