Mitochondrial tRNAGln 4394C>T Mutation May Contribute to the Clinical Expression of 1555A>G-Induced Deafness

Genes (Basel). 2022 Oct 5;13(10):1794. doi: 10.3390/genes13101794.


The mitochondrial 1555A>G mutation plays a critical role in aminoglycoside-induced and non-syndromic hearing loss (AINSHL). Previous studies have suggested that mitochondrial secondary variants may modulate the clinical expression of m.1555A>G-induced deafness, but the molecular mechanism has remained largely undetermined. In this study, we investigated the contribution of a deafness-associated tRNAGln 4394C>T mutation to the clinical expression of the m.1555A>G mutation. Interestingly, a three-generation family with both the m.1555A>G and m.4394C>T mutations exhibited a higher penetrance of hearing loss than another family harboring only the m.1555A>G mutation. At the molecular level, the m.4394C>T mutation resides within a very conserved nucleotide of tRNAGln, which forms a new base-pairing (7T-66A) and may affect tRNA structure and function. Using trans-mitochondrial cybrid cells derived from three subjects with both the m.1555A>G and m.4394C>T mutations, three patients with only the m.1555A>G mutation and three control subjects without these primary mutations, we observed that cells with both the m.1555A>G and m.4394C>T mutations exhibited more severely impaired mitochondrial functions than those with only the m.1555A>G mutation. Furthermore, a marked decrease in mitochondrial RNA transcripts and respiratory chain enzymes was observed in cells harboring both the m.1555A>G and m.4394C>T mutations. Thus, our data suggest that the m.4394C>T mutation may play a synergistic role in the m.1555A>G mutation, enhancing mitochondrial dysfunctions and contributing to a high penetrance of hearing loss in families with both mtDNA pathogenic mutations.

Keywords: deafness; m.1555A>G mutation; mt-tRNAGln 4394C>T mutation; synergistic effect.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aminoglycosides
  • DNA, Mitochondrial / genetics
  • Deafness* / chemically induced
  • Deafness* / genetics
  • Hearing Loss* / chemically induced
  • Hearing Loss* / genetics
  • Humans
  • Mutation
  • Nucleotides / adverse effects
  • RNA, Mitochondrial
  • RNA, Transfer, Gln


  • RNA, Mitochondrial
  • RNA, Transfer, Gln
  • Aminoglycosides
  • DNA, Mitochondrial
  • Nucleotides

Grants and funding

This work was supported by grants from the Health Commission of Zhejiang Province (2021RC022), Hangzhou Bureau of Science and Technology (20201203B210) and Hangzhou Municipal Health Commission (ZD20220010).