CAJ | 학술논문

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、B4c1b1、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ND1L89T和CO3 A200T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.
목적 통과대모계유전비종합정성이롱가계림상화분자유전학특정분석,진일보탐토선립체12S rRNA기인대모계유전약물성이롱적영향.방법 수집5개비종합정성이롱환자가계,제취기인조DNA,연후진행선립체DNA전서렬화간극련접단백β2(gap junction protein beta 2,GJB2)기인확증병측서분석.결과 5개가계내화가계간적모계성원재은력손실、발병년령화은력곡선상존재교대차이.5개가계이롱발생적외현솔분별위17.6%、50.0%、66.7%、31.3%화23.1%,평균외현솔시37.7%.선립체전서렬현시가계간존재이지적1555A＞G돌변화불동적다태성위점,분별속우동아인군D4b2b、B4c1b1、F3、C1、D5a단배형.저5개가계몰유휴대이지적선립체DNA계발돌변,단발현료2개보수성교고적ND1L89T화CO3 A200T돌변.이차,GJB2기인상미발현여이롱상관적돌변.결론 저5개모계유전비종합정성이롱가계중,선립체DNA계발돌변、GJB2기인가능몰유영향1555A＞G적표형표체.연이,안기당대류항생소、선립체DNA다태성급기타핵수식기인가능대저5개이롱가계적표형표체기도수식작용.
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, B4c1b1, F3, C1 and D5a, respectively. Of these variants, ND1 L89T and CO3 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.