The tRNAGly T10003C mutation in mitochondrial haplogroup M11b in a Chinese family with diabetes decreases the steady-state level of tRNAGly, increases aberrant reactive oxygen species production, and reduces mitochondrial membrane potential
The tRNAGly T10003C mutation in mitochondrial haplogroup M11b in a Chinese family with diabetes decreases the steady-state level of tRNAGly, increases aberrant reactive oxygen species production, and reduces mitochondrial membrane potential
复制标题
DOI：
10.1007/s11010-015-2493-0
复制
发表时间：
2015-10-01
影响因子：
4.3
通讯作者：
Lu, Jianxin
中科院分区：
文献类型：
--
作者：
Li, Wei;Wen, Chaowei;Lu, Jianxin
线粒体糖尿病主要起源于位于母系传播的线粒体tRNA编码基因的突变。在对中国汉族人群进行的2型糖尿病遗传筛查中，我们发现了一个疑似母系遗传的糖尿病家系。先证者的线粒体基因组进行了分析，使用DNA测序。共鉴定出42个已知核苷变化和1个新变体，并将整个线粒体DNA序列分配给单倍群M11 b。系统进化分析表明，该菌株编码tRNA的基因（Gly）在高度保守的位点上发生了一个同源突变，即10003 T> C转换。结果表明，与野生型细胞相比，该突变显著影响了细胞内tRNA（Gly）的稳态水平，tRNA（Gly）含量降低了97%，活性氧产生增加，线粒体膜电位、mtDNA拷贝数和细胞耗氧率显著降低。线粒体tRNA（Gly）基因10003 T> C突变可能是一种与母系遗传性糖尿病发病相关的突变。
Mitochondrial diabetes originates mainly from mutations located in maternally transmitted, mitochondrial tRNA-coding genes. In a genetic screening program of type 2 diabetes conducted with a Chinese Han population, we found one family with suggestive maternally transmitted diabetes. The proband's mitochondrial genome was analyzed using DNA sequencing. Total 42 known nucleoside changes and 1 novel variant were identified, and the entire mitochondrial DNA sequence was assigned to haplogroup M11b. Phylogenetic analysis showed that a homoplasmic mutation, 10003T > C transition, occurred at the highly conserved site in the gene encoding tRNA(Gly). Using a transmitochondrial cybrid cell line harboring this mutation, we observed that the steady-state level of tRNA(Gly) significantly affected and the amount of tRNA(Gly) decreased by 97 %, production of reactive oxygen species was enhanced, and mitochondrial membrane potential, mtDNA copy number and cellular oxygen consumption rate were remarkably decreased compared with wild-type cybrid cells. The homoplasmic 10003T > C mutation in the mitochondrial tRNA(Gly) gene suggested to be as a pathogenesis-related mutation which might contribute to the maternal inherited diabetes in the Han Chinese family.