Mutations of the mitochondrial-tRNA modifier MTO1 cause hypertrophic cardiomyopathy and lactic acidosis

Am J Hum Genet. 2012 Jun 8;90(6):1079-87. doi: 10.1016/j.ajhg.2012.04.011. Epub 2012 May 17.


Dysfunction of mitochondrial respiration is an increasingly recognized cause of isolated hypertrophic cardiomyopathy. To gain insight into the genetic origin of this condition, we used next-generation exome sequencing to identify mutations in MTO1, which encodes mitochondrial translation optimization 1. Two affected siblings carried a maternal c.1858dup (p.Arg620Lysfs(∗)8) frameshift and a paternal c.1282G>A (p.Ala428Thr) missense mutation. A third unrelated individual was homozygous for the latter change. In both humans and yeast, MTO1 increases the accuracy and efficiency of mtDNA translation by catalyzing the 5-carboxymethylaminomethylation of the wobble uridine base in three mitochondrial tRNAs (mt-tRNAs). Accordingly, mutant muscle and fibroblasts showed variably combined reduction in mtDNA-dependent respiratory chain activities. Reduced respiration in mutant cells was corrected by expressing a wild-type MTO1 cDNA. Conversely, defective respiration of a yeast mto1Δ strain failed to be corrected by an Mto1(Pro622∗) variant, equivalent to human MTO1(Arg620Lysfs∗8), whereas incomplete correction was achieved by an Mto1(Ala431Thr) variant, corresponding to human MTO1(Ala428Thr). The respiratory yeast phenotype was dramatically worsened in stress conditions and in the presence of a paromomycin-resistant (P(R)) mitochondrial rRNA mutation. Lastly, in vivo mtDNA translation was impaired in the mutant yeast strains.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acidosis, Lactic / genetics*
  • Base Sequence
  • Cardiomyopathy, Hypertrophic / genetics*
  • Carrier Proteins / genetics*
  • DNA Mutational Analysis*
  • DNA, Mitochondrial / genetics
  • Fibroblasts / metabolism
  • Homozygote
  • Humans
  • Mitochondria / metabolism*
  • Molecular Sequence Data
  • Mothers
  • Mutation
  • Mutation, Missense
  • Nucleic Acid Conformation
  • Oxidative Phosphorylation
  • Paromomycin / pharmacology
  • Phenotype
  • Phosphorylation
  • RNA, Ribosomal / metabolism
  • RNA, Transfer / genetics*
  • RNA-Binding Proteins
  • Respiration
  • Saccharomyces cerevisiae / genetics


  • Carrier Proteins
  • DNA, Mitochondrial
  • MTO1 protein, human
  • RNA, Ribosomal
  • RNA-Binding Proteins
  • Paromomycin
  • RNA, Transfer