Contribution of a mitochondrial tyrosyl-tRNA synthetase mutation to the phenotypic expression of the deafness-associated tRNASer(UCN) 7511A>G mutation

J Biol Chem. 2019 Dec 13;294(50):19292-19305. doi: 10.1074/jbc.RA119.010598. Epub 2019 Nov 4.


Nuclear modifier genes have been proposed to modify the phenotypic expression of mitochondrial DNA mutations. Using a targeted exome-sequencing approach, here we found that the p.191Gly>Val mutation in mitochondrial tyrosyl-tRNA synthetase 2 (YARS2) interacts with the tRNASer(UCN) 7511A>G mutation in causing deafness. Strikingly, members of a Chinese family bearing both the YARS2 p.191Gly>Val and m.7511A>G mutations displayed much higher penetrance of deafness than those pedigrees carrying only the m.7511A>G mutation. The m.7511A>G mutation changed the A4:U69 base-pairing to G4:U69 pairing at the aminoacyl acceptor stem of tRNASer(UCN) and perturbed tRNASer(UCN) structure and function, including an increased melting temperature, altered conformation, instability, and aberrant aminoacylation of mutant tRNA. Using lymphoblastoid cell lines derived from symptomatic and asymptomatic members of these Chinese families and control subjects, we show that cell lines harboring only the m.7511A>G or p.191Gly>Val mutation revealed relatively mild defects in tRNASer(UCN) or tRNATyr metabolism, respectively. However, cell lines harboring both m.7511A>G and p.191Gly>Val mutations displayed more severe defective aminoacylations and lower tRNASer(UCN) and tRNATyr levels, aberrant aminoacylation, and lower levels of other tRNAs, including tRNAThr, tRNALys, tRNALeu(UUR), and tRNASer(AGY), than those in the cell lines carrying only the m.7511A>G or p.191Gly>Val mutation. Furthermore, mutant cell lines harboring both m.7511A>G and p.191Gly>Val mutations exhibited greater decreases in the levels of mitochondrial translation, respiration, and mitochondrial ATP and membrane potentials, along with increased production of reactive oxygen species. Our findings provide molecular-level insights into the pathophysiology of maternally transmitted deafness arising from the synergy between tRNASer(UCN) and mitochondrial YARS mutations.

Keywords: RNA metabolism; genetic disorder; hearing; hearing loss; maternal inheritance; maternally transmitted deafness; mitochondrial DNA (mtDNA); mitochondrial disease; mitochondrial metabolism; mitochondrial respiratory chain complex; mitochondrial tRNA; mitochondrial translation; mutation; oxidative stress; pathogenesis; pathophysiology; reactive oxygen species (ROS); synergy; tRNASer(UCN); transfer RNA (tRNA); translation; tyrosyl-tRNA synthetase 2 (YARS2).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Asian People
  • Cells, Cultured
  • DNA, Mitochondrial / genetics
  • DNA, Mitochondrial / metabolism
  • Female
  • Humans
  • Male
  • Mitochondria / enzymology*
  • Mutation*
  • Pedigree
  • Phenotype
  • RNA, Transfer, Ser / genetics*
  • Tyrosine-tRNA Ligase / genetics*
  • Tyrosine-tRNA Ligase / metabolism


  • DNA, Mitochondrial
  • RNA, Transfer, Ser
  • Tyrosine-tRNA Ligase