title: Maternally inherited diabetes is associated with a homoplasmic T10003C mutation in the mitochondrial tRNA(Gly) gene.
abstract: In this report, we investigate molecular pathogenic mechanism of a diabetes-associated homoplasmic mitochondrial tRNA mutation in a Han Chinese family with maternally transmitted diabetes mellitus. Of 10 adult matrilineal relatives, 5 individuals suffered from diabetes (4 subjects with only diabetes, one subject with both diabetes and hearing impairment), while other five matrilineal relatives (one with hearing loss) had glucose intolerance. The average age at onset of diabetes in matrilineal relatives was 50 years. Molecular analysis of their mitochondrial genomes identified the novel homoplasmic T10003C mutation in the tRNA(Gly) gene belonging to haplogroup M11b. The T10003C mutation is expected to form a base-pairing (13C-22G) at the highly conserved D-stem of tRNA(Gly), thereby affecting secondary structure and function of this tRNA. A tRNA Northern analysis revealed that the T10003C mutation caused ~70% reduction in the steady-state level of tRNA(Gly). An in vivo translation analysis showed ~33% reduction in the rate of mitochondrial translation in mutant cells. Oxygen consumption analysis showed the defects in overall respiratory capacity or the ATP-linked, proton leak, and maximal respiration in mutant cells. As a result, the cellular energy deficiency contributes to the development of diabetes in subjects carrying the T10003C mutation. These data provide the first direct evidence that the tRNA(Gly) mutation might be associated with diabetes. Thus, our findings may provide new insights into the understanding of pathophysiology of maternally inherited diabetes.
authors.affiliation: Institute of Genetics, Zhejiang University, Hangzhou, Zhejiang, China.
authors.forename: Hao
authors.initials: H
authors.lastname: Liu
authors.affiliation: Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
authors.forename: Ronghua
authors.initials: R
authors.lastname: Li
authors.affiliation: Attardi Institute of Mitochondrial Biomedicine, Wenzhou Medical University, Wenzhou, Zhejiang, China; Department of Laboratory Medicine, The Provincial People's Hospital of Zhejiang, Hangzhou, Zhejiang, China.
authors.forename: Weixing
authors.initials: W
authors.lastname: Li
authors.affiliation: Institute of Genetics, Zhejiang University, Hangzhou, Zhejiang, China.
authors.forename: Meng
authors.initials: M
authors.lastname: Wang
authors.affiliation: Attardi Institute of Mitochondrial Biomedicine, Wenzhou Medical University, Wenzhou, Zhejiang, China.
authors.forename: Jingzhang
authors.initials: J
authors.lastname: Ji
authors.affiliation: Institute of Genetics, Zhejiang University, Hangzhou, Zhejiang, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Zheng
authors.affiliation: Institute of Genetics, Zhejiang University, Hangzhou, Zhejiang, China.
authors.forename: Zhuochao
authors.initials: Z
authors.lastname: Mao
authors.affiliation: Division of Pathology and Pediatrics, Rady Children's Hospital, University of California San Diego, San Diego, CA 92123, USA.
authors.forename: Jun Qin
authors.initials: JQ
authors.lastname: Mo
authors.affiliation: Institute of Genetics, Zhejiang University, Hangzhou, Zhejiang, China.
authors.forename: Pingping
authors.initials: P
authors.lastname: Jiang
authors.affiliation: Attardi Institute of Mitochondrial Biomedicine, Wenzhou Medical University, Wenzhou, Zhejiang, China.
authors.forename: Jianxin
authors.initials: J
authors.lastname: Lu
authors.affiliation: Institute of Genetics, Zhejiang University, Hangzhou, Zhejiang, China; Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA. Electronic address: gminxin88@zju.edu.cn.
authors.forename: Min-Xin
authors.initials: MX
authors.lastname: Guan
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000328:Adult; D000368:Aged; D044466:Asian People; D015152:Blotting, Northern; D019069:Cell Respiration; D003920:Diabetes Mellitus / Q000235:genetics*; D004734:Energy Metabolism; D005260:Female; D020869:Gene Expression Profiling; D050259:Genes, Mitochondrial; D006801:Humans; D008297:Male; D008875:Middle Aged; D028361:Mitochondrial Diseases / Q000235:genetics*; D009154:Mutation; D009690:Nucleic Acid Conformation; D014176:Protein Biosynthesis; D012353:RNA, Transfer, Gly / Q000737:chemistry / Q000235:genetics*; D055815:Young Adult
chemical_list: D012353:RNA, Transfer, Gly; D000255:Adenosine Triphosphate
keywords: Deafness; Diabetes; Maternal transmission; Mitochondria; Pathophysiology; tRNA mutation