Maternally inherited diabetes is associated with a homoplasmic T10003C mutation in the mitochondrial tRNAGly gene

Líu, Hao; Li, Ronghua; Li, Weixing; Wang, Meng; Ji, Jingzhang; Zheng, Jing; Mao, Zhuochao; Mo, Jun Qin; Jiang, Pingping; Lü, Jianxin; Guan, Min‐Xin

doi:10.1016/j.mito.2015.01.004

Cited by 27 publications

(24 citation statements)

References 54 publications

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“…In this family, obesity started setting in at 9.3 years age. In contrast, the affected subjects carrying the m.5802A>G mutation suffered from being overweight or obese, like those exhibited in T2DM patients carrying m.10003T>C mutation [6]. Furthermore, a very low penetrance of obesity subjects was observed in this Chinese pedigree harboring the m.5802A>G mutation.…”

Section: Acc-stem D-stem D-loop D-stem Ac-stem Anticd-loop Ac-stem V-mentioning

confidence: 60%

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Obesity associated with a novel mitochondrial tRNACys 5802A>G mutation in a Chinese family

et al. 2020

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A Chinese family with matrilineally inherited obesity was assessed and its clinical, genetic, and molecular profiling was conducted. Obesity was observed in matrilineal relatives (3 out of 7) of a single generation (of 3 alive generations) in this family. On pedigree analysis and sequencing of their mitochondrial DNA (mtDNA), a novel homoplasmic mutation of the mitochondrial tRNA Cys gene (5802A>G) was identified in these individuals. This mutation correlated with a destabilized conserved base pair in this tRNA anticodon stem. Position 30 is known to be crucial for carrying out effective codon recognition and stability of tRNA. In accordance with the importance of this conserved site, we observed that the predicted structure of tRNA Cys with the mutation was noticeably remodeled in a molecular dynamics simulation when compared with the isoform of the wild-type. All other 46 mutations observed in the individual's mtDNA were known variants belonging to haplogroup D4. Thus, this is the first report that provides evidence of the association between a mutation in tRNA and an enhanced risk of maternally transmissible obesity, offering more insights into obesity and its underlying nature.

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Section: Acc-stem D-stem D-loop D-stem Ac-stem Anticd-loop Ac-stem V-mentioning

confidence: 60%

“…It was indicated that mutations in mtDNA may be associated with obesity. For instance, the tRNA Thr mutation m.10003T>C, as well as the tRNA Glu mutations m.14709T>C, and m.14692A>G have been associated with such disease [6][7][8].…”

Section: Introductionmentioning

confidence: 99%

Obesity associated with a novel mitochondrial tRNACys 5802A>G mutation in a Chinese family

et al. 2020

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“…Of these, the m.1555A > G and m.1494C > T mutations in the 12S rRNA gene have been associated with both aminoglycoside-induced and nonsyndromic deafness in many families worldwide (3,4,11,12). The most prevalent mtDNA mutations associated with syndromic deafness are the MELAS-associated m.3243A > G mutation in the mt–tRNA Leu(UUR) gene (13) and MERRF-associated m.8344A > G mutation in the mt–tRNA Lys gene (14), while the nonsyndromic deafness-associated mtDNA mutations included the mt–tRNA Ser(UCN) 7445A > G, 7472insC, 7505T > C and 7511T > C, mt–tRNA His 12201T > C, mt–tRNA Gly 10003T > C and mt–tRNA Ile 4295A > G mutations (15–21). These mt–tRNA mutations altered their structures and functions, including the processing of the mt–tRNA from the primary transcripts, stability of the folded secondary structure, the charging of the mt–tRNA, or the codon–anticodon interaction in the process of translation (5,22,23).…”

Section: Introductionmentioning

confidence: 99%

A deafness-associated tRNA^Aspmutation alters the m¹G37 modification, aminoacylation and stability of tRNA^Aspand mitochondrial function

et al. 2016

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In this report, we investigated the pathogenic mechanism underlying the deafness-associated mitochondrial(mt) tRNAAsp 7551A > G mutation. The m.7551A > G mutation is localized at a highly conserved nucleotide(A37), adjacent (3′) to the anticodon, which is important for the fidelity of codon recognition and stabilization in functional tRNAs. It was anticipated that the m.7551A > G mutation altered the structure and function of mt-tRNAAsp. The primer extension assay demonstrated that the m.7551A > G mutation created the m1G37 modification of mt-tRNAAsp. Using cybrid cell lines generated by transferring mitochondria from lymphoblastoid cell lines derived from a Chinese family into mitochondrial DNA(mtDNA)-less (ρo) cells, we demonstrated the significant decreases in the efficiency of aminoacylation and steady-state level of mt-tRNAAsp in mutant cybrids, compared with control cybrids. A failure in metabolism of mt-tRNAAsp caused the variable reductions in mtDNA-encoded polypeptides in mutant cybrids. Impaired mitochondrial translation led to the respiratory phenotype in mutant cybrids. The respiratory deficiency lowed mitochondrial adenosine triphosphate production and increased the production of oxidative reactive species in mutant cybrids. Our data demonstrated that mitochondrial dysfunctions caused by the m.7551A > G mutation are associated with deafness. Our findings may provide new insights into the pathophysiology of maternally transmitted deafness that was manifested by altered nucleotide modification of mitochondrial tRNA.

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“…Liu et al [29] have provided the evidence that 10003T[C mutation could result in the marked decease the levels of tRNA Gly and mitochondrial protein synthesis defect with respiration deficiency. In this study, we also found the remarkable decrease of oxygen consumption rate (OCR) with reduced mtDNA copy number.…”

Section: Discussionmentioning

confidence: 99%

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

Wei

Wen

et al. 2015

Mol Cell Biochem

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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.

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Maternally inherited diabetes is associated with a homoplasmic T10003C mutation in the mitochondrial tRNAGly gene

Cited by 27 publications

References 54 publications

Obesity associated with a novel mitochondrial tRNACys 5802A>G mutation in a Chinese family

Obesity associated with a novel mitochondrial tRNACys 5802A>G mutation in a Chinese family

A deafness-associated tRNA^Aspmutation alters the m¹G37 modification, aminoacylation and stability of tRNA^Aspand mitochondrial function

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

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Maternally inherited diabetes is associated with a homoplasmic T10003C mutation in the mitochondrial tRNAGly gene

Cited by 27 publications

References 54 publications

Obesity associated with a novel mitochondrial tRNACys 5802A&gt;G mutation in a Chinese family

Obesity associated with a novel mitochondrial tRNACys 5802A&gt;G mutation in a Chinese family

A deafness-associated tRNAAspmutation alters the m1G37 modification, aminoacylation and stability of tRNAAspand mitochondrial function

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

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Obesity associated with a novel mitochondrial tRNACys 5802A>G mutation in a Chinese family

Obesity associated with a novel mitochondrial tRNACys 5802A>G mutation in a Chinese family

A deafness-associated tRNA^Aspmutation alters the m¹G37 modification, aminoacylation and stability of tRNA^Aspand mitochondrial function