title: Mutations of the mitochondrial-tRNA modifier MTO1 cause hypertrophic cardiomyopathy and lactic acidosis.
abstract: 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.
authors.affiliation: Unit of Molecular Neurogenetics, Fondazione IRCCS, Milan, Italy.
authors.forename: Daniele
authors.initials: D
authors.lastname: Ghezzi
authors.forename: Enrico
authors.initials: E
authors.lastname: Baruffini
authors.forename: Tobias B
authors.initials: TB
authors.lastname: Haack
authors.forename: Federica
authors.initials: F
authors.lastname: Invernizzi
authors.forename: Laura
authors.initials: L
authors.lastname: Melchionda
authors.forename: Cristina
authors.initials: C
authors.lastname: Dallabona
authors.forename: Tim M
authors.initials: TM
authors.lastname: Strom
authors.forename: Rossella
authors.initials: R
authors.lastname: Parini
authors.forename: Alberto B
authors.initials: AB
authors.lastname: Burlina
authors.forename: Thomas
authors.initials: T
authors.lastname: Meitinger
authors.forename: Holger
authors.initials: H
authors.lastname: Prokisch
authors.forename: Ileana
authors.initials: I
authors.lastname: Ferrero
authors.forename: Massimo
authors.initials: M
authors.lastname: Zeviani
mesh_terms: D000140:Acidosis, Lactic / Q000235:genetics*; D001483:Base Sequence; D002312:Cardiomyopathy, Hypertrophic / Q000235:genetics*; D002352:Carrier Proteins / Q000235:genetics*; D004252:DNA Mutational Analysis; D004272:DNA, Mitochondrial / Q000235:genetics; D005347:Fibroblasts / Q000378:metabolism; D006720:Homozygote; D006801:Humans; D008928:Mitochondria / Q000378:metabolism*; D008969:Molecular Sequence Data; D009035:Mothers; D009154:Mutation; D020125:Mutation, Missense; D009690:Nucleic Acid Conformation; D010085:Oxidative Phosphorylation; D010303:Paromomycin / Q000494:pharmacology; D010641:Phenotype; D010766:Phosphorylation; D012335:RNA, Ribosomal / Q000378:metabolism; D012343:RNA, Transfer / Q000235:genetics*; D016601:RNA-Binding Proteins; D012119:Respiration; D012441:Saccharomyces cerevisiae / Q000235:genetics
chemical_list: D002352:Carrier Proteins; D004272:DNA, Mitochondrial; C492006:MTO1 protein, human; D012335:RNA, Ribosomal; D016601:RNA-Binding Proteins; D010303:Paromomycin; D012343:RNA, Transfer