American journal of human genetics, 2012-06-08, Vol.90 (6), p.1079-1087
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 Mto1Pro622∗ variant, equivalent to human MTO1Arg620Lysfs∗8, whereas incomplete correction was achieved by an Mto1Ala431Thr variant, corresponding to human MTO1Ala428Thr. The respiratory yeast phenotype was dramatically worsened in stress conditions and in the presence of a paromomycin-resistant (PR) mitochondrial rRNA mutation. Lastly, in vivo mtDNA translation was impaired in the mutant yeast strains.
Acidosis, Lactic - genetics ; Base Sequence ; Biological and medical sciences ; Cardiology. Vascular system ; Cardiomyopathy, Hypertrophic ; Cardiomyopathy, Hypertrophic - genetics ; Carrier Proteins - genetics ; Causes of ; DNA Mutational Analysis ; DNA, Mitochondrial - genetics ; Fibroblasts - metabolism ; Fundamental and applied biological sciences. Psychology ; Gene mutations ; Genetic aspects ; Genetic translation ; Genetics of eukaryotes. Biological and molecular evolution ; Heart ; Homozygote ; Humans ; Lactic acidosis ; Medical genetics ; Medical sciences ; Mitochondria ; Mitochondria - metabolism ; Mitochondrial DNA ; Molecular and cellular biology ; Molecular Sequence Data ; Mothers ; Mutation ; Mutation, Missense ; Myocarditis. Cardiomyopathies ; Nucleic Acid Conformation ; Oxidative Phosphorylation ; Paromomycin - pharmacology ; Phenotype ; Phosphorylation ; Report ; Research ; Respiration ; RNA, Ribosomal - metabolism ; RNA, Transfer - genetics ; Saccharomyces cerevisiae - genetics ; Transfer RNA
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