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

Daniele Ghezzi, Enrico Baruffini, Tobias B. Haack, Federica Invernizzi, Laura Melchionda, Cristina Dallabona, Tim M. Strom, Rossella Parini, Alberto B. Burlina, Thomas Meitinger, Holger Prokisch, Ileana Ferrero, Massimo Zeviani

Research output: Contribution to journalArticle

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.Arg620Lysfs8) 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 Arg620Lysfs8, 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.

Original languageEnglish
Pages (from-to)1079-1087
Number of pages9
JournalAmerican Journal of Human Genetics
Volume90
Issue number6
DOIs
Publication statusPublished - Jun 8 2012

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Lactic Acidosis
Hypertrophic Cardiomyopathy
Transfer RNA
Yeasts
Mitochondrial DNA
Respiration
Mutation
Paromomycin
Exome
Uridine
Missense Mutation
Electron Transport
Complementary DNA
Fibroblasts
Mothers
Phenotype
Muscles

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Ghezzi, D., Baruffini, E., Haack, T. B., Invernizzi, F., Melchionda, L., Dallabona, C., ... Zeviani, M. (2012). Mutations of the mitochondrial-tRNA modifier MTO1 cause hypertrophic cardiomyopathy and lactic acidosis. American Journal of Human Genetics, 90(6), 1079-1087. https://doi.org/10.1016/j.ajhg.2012.04.011

Mutations of the mitochondrial-tRNA modifier MTO1 cause hypertrophic cardiomyopathy and lactic acidosis. / Ghezzi, Daniele; Baruffini, Enrico; Haack, Tobias B.; Invernizzi, Federica; Melchionda, Laura; Dallabona, Cristina; Strom, Tim M.; Parini, Rossella; Burlina, Alberto B.; Meitinger, Thomas; Prokisch, Holger; Ferrero, Ileana; Zeviani, Massimo.

In: American Journal of Human Genetics, Vol. 90, No. 6, 08.06.2012, p. 1079-1087.

Research output: Contribution to journalArticle

Ghezzi, D, Baruffini, E, Haack, TB, Invernizzi, F, Melchionda, L, Dallabona, C, Strom, TM, Parini, R, Burlina, AB, Meitinger, T, Prokisch, H, Ferrero, I & Zeviani, M 2012, 'Mutations of the mitochondrial-tRNA modifier MTO1 cause hypertrophic cardiomyopathy and lactic acidosis', American Journal of Human Genetics, vol. 90, no. 6, pp. 1079-1087. https://doi.org/10.1016/j.ajhg.2012.04.011
Ghezzi, Daniele ; Baruffini, Enrico ; Haack, Tobias B. ; Invernizzi, Federica ; Melchionda, Laura ; Dallabona, Cristina ; Strom, Tim M. ; Parini, Rossella ; Burlina, Alberto B. ; Meitinger, Thomas ; Prokisch, Holger ; Ferrero, Ileana ; Zeviani, Massimo. / Mutations of the mitochondrial-tRNA modifier MTO1 cause hypertrophic cardiomyopathy and lactic acidosis. In: American Journal of Human Genetics. 2012 ; Vol. 90, No. 6. pp. 1079-1087.
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