Key result
Dual mitochondrial mutations synergize to worsen mitochondrial dysfunction and increase HCM penetrance.
Why the study?
Mutations in mitochondrial tRNA are associated with hypertrophic cardiomyopathy, but their molecular mechanisms remain largely undetermined.
Observational
The m.12234A>G mutation acts synergistically with the m.4263A>G mutation to trigger severe mitochondrial dysfunction, contributing to high penetrance of hypertrophic cardiomyopathy.
Should not yet alter HCM counseling for these variants; leaves open synergistic mt-tRNA effects on penetrance.
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‐tRNA Ser(AGY) 12234A > G mutation to the phenotypic expression of the mt‐tRNA Ile 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 tRNA Ile 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 tRNA Ser(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.
No takes yet. Share an insight, caveat, or question.
Liu et al. (2026) conducted an observational in Hypertrophic cardiomyopathy. Co-occurrence of m.12234A>G and m.4263A>G mutations vs. m.4263A>G mutation alone was evaluated on Mitochondrial dysfunction and penetrance of HCM. The m.12234A>G mutation acted in synergy with the m.4263A>G mutation, triggering more severe mitochondrial dysfunction and contributing to a higher penetrance of hypertrophic cardiomyopathy.
Synapse has enriched 5 closely related papers on similar clinical questions. Consider them for comparative context: