Mitochondrial tRNASer(AGY) 12234A > G Mutation May Contribute to the Clinical Expression of Hypertrophic Cardiomyopathy‐Associated tRNAIle 4263A > G Mutation

Abstract

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.