Central Laboratory, Hangzhou First People's Hospital, Zhejiang University, School of Medicine, Hangzhou, China.
Department of Otolaryngology, Hangzhou First People's Hospital, Zhejiang University, School of Medicine, Hangzhou, China.
Curr Mol Med. 2019;19(2):136-146. doi: 10.2174/1566524019666190308121552.
Mutations in mitochondrial tRNA (mt-tRNA) genes have been found to be associated with both syndromic and non-syndromic hearing impairment. However, the pathophysiology underlying mt-tRNA mutations in clinical expression of hearing loss remains poorly understood.
The aim of this study was to explore the potential association between mttRNA mutations and hearing loss.
We reported here the molecular features of a pedigree with maternally transmitted non-syndromic hearing loss. Among 12 matrilineal relatives, five of them suffered variable degree of hearing impairment, but none of them had any medical history of using aminoglycosides antibiotics (AmAn). Genetic screening of the complete mitochondrial genomes from the matrilineal relatives identified the coexistence of mt-tRNAHis G12192A and mt-tRNAThr G15927A mutations, together with a set of polymorphisms belonging to human mitochondrial haplogroup B5b1b. Interestingly, the G12192A mutation occurred 2-bp from the 3' end of the TψC loop of mt-tRNAHis, which was evolutionarily conserved from various species. In addition, the well-known G15927A mutation, which disrupted the highly conserved C-G base-pairing at the anticodon stem of mt-tRNAThr, may lead to the failure in mt-tRNA metabolism. Furthermore, a significant decreased in ATP production and an increased ROS generation were observed in polymononuclear leukocytes (PMNs) which were isolated from the deaf patients carrying these mt-tRNA mutations, suggested that the G12192A and G15927A mutations may cause mitochondrial dysfunction that was responsible for deafness. However, the absence of any functional mutations/variants in GJB2, GJB3, GJB6 and TRMU genes suggested that the nuclear genes may not play important roles in the clinical expression of non-syndromic hearing loss in this family.
Our data indicated that mt-tRNAHis G12192A mutation may increase the penetrance and expressivity of deafness-associated m-tRNAThr G15927A mutation in this family.
线粒体 tRNA（mt-tRNA）基因突变与综合征性和非综合征性听力障碍有关。然而，mt-tRNA 突变在听力损失临床表现中的病理生理学仍知之甚少。
本研究旨在探讨 mt-tRNA 突变与听力损失之间的潜在关联。
我们在这里报告了一个具有母系遗传性非综合征性听力损失的家系的分子特征。在 12 位母系亲属中，有 5 位患有不同程度的听力障碍，但他们均无使用氨基糖苷类抗生素（AmAn）的医疗史。对母系亲属的完整线粒体基因组进行遗传筛查，发现 mt-tRNAHis G12192A 和 mt-tRNAThr G15927A 突变共存，以及一组属于人类线粒体单倍群 B5b1b 的多态性。有趣的是，G12192A 突变发生在 mt-tRNAHis 的 TψC 环 3' 端的 2 个碱基处，从各种物种进化上保守。此外，破坏 mt-tRNAThr 反密码子茎高度保守的 C-G 碱基对的众所周知的 G15927A 突变，可能导致 mt-tRNA 代谢失败。此外，从携带这些 mt-tRNA 突变的耳聋患者分离的多形核白细胞（PMNs）中观察到 ATP 产生显著减少和 ROS 生成增加，表明 G12192A 和 G15927A 突变可能导致线粒体功能障碍，从而导致耳聋。然而，在 GJB2、GJB3、GJB6 和 TRMU 基因中没有发现任何功能突变/变体，这表明核基因在这个家族的非综合征性听力损失的临床表现中可能不起重要作用。
我们的数据表明，mt-tRNAHis G12192A 突变可能增加与耳聋相关的 mt-tRNAThr G15927A 突变在这个家族中的外显率和表现度。
