Mitochondrial tRNA(Ser(AGY)) 12234A > G Mutation May Contribute to the Clinical Expression of Hypertrophic Cardiomyopathy-Associated tRNA(Ile) 4263A > G Mutation.

摘要

Mutations in mitochondrial tRNA (mt-tRNA) are found to be associated with hypertrophic cardiomyopathy (HCM), but their molecular mechanisms remain largely undetermined. In this study, we investigated the contribution of a novel HCM-related mt-tRNASer(AGY) 12234A > G mutation to the phenotypic expression of the mt-tRNAIle 4263A > G mutation in two genetically unrelated Han Chinese pedigrees. Strikingly, the penetrance and expressivity of one pedigree (HCM2) with both m.4263A > G and m.12234A > G mutations are much higher than another pedigree (HCM1) with only m.4263A > G mutation. By molecular level, the homoplasmic m.4263A > G mutation is located at the processing site for the tRNAIle 5 '-end precursor, disrupting a conserved Watson-Crick base pairing (1A-69T) which is believed to cause mitochondrial dysfunction. Moreover, the heteroplasmic m.12234A > G mutation occurs at an extremely conserved nucleotide in the anticodon stem of tRNASer(AGY), a position which is critical for tRNA structure and function. Using trans-mitochondrial cell models, we demonstrated that cybrids with both mt-tRNA mutations exhibited more severe mitochondrial dysfunctions than cybrids with only the m.4263A > G mutation. Furthermore, a marked decrease in mt-RNA transcripts was observed in cells harboring both m.4263A > G and m.12234A > G mutations. Taken together, our study indicated that the m.12234A > G mutation acted in synergy with the m.4263A > G mutation, triggering mitochondrial dysfunctions and contributing to a high penetrance of HCM in a pedigree harboring both mtDNA mutations.