MTO1 mutations are associated with hypertrophic cardiomyopathy and lactic acidosis and cause respiratory chain deficiency in humans and yeast.

TitleMTO1 mutations are associated with hypertrophic cardiomyopathy and lactic acidosis and cause respiratory chain deficiency in humans and yeast.
Publication TypeJournal Article
Year of Publication2013
AuthorsBaruffini, E, Dallabona, C, Invernizzi, F, Yarham, JW, Melchionda, L, Blakely, EL, Lamantea, E, Donnini, C, Santra, S, Vijayaraghavan, S, Roper, HP, Burlina, A, Kopajtich, R, Walther, A, Strom, TM, Haack, TB, Prokisch, H, Taylor, RW, Ferrero, I, Zeviani, M, Ghezzi, D
JournalHum Mutat
Date Published2013 Nov
KeywordsAcidosis, Lactic, Adolescent, Age of Onset, Amino Acid Sequence, Brain, Cardiomyopathy, Hypertrophic, Carrier Proteins, Child, Child, Preschool, DNA Mutational Analysis, Electron Transport Chain Complex Proteins, Female, Humans, Infant, Infant, Newborn, Magnetic Resonance Imaging, Male, Models, Molecular, Molecular Sequence Data, Mutation, Pedigree, Protein Conformation, Sequence Alignment, Yeasts, Young Adult

We report three families presenting with hypertrophic cardiomyopathy, lactic acidosis, and multiple defects of mitochondrial respiratory chain (MRC) activities. By direct sequencing of the candidate gene MTO1, encoding the mitochondrial-tRNA modifier 1, or whole exome sequencing analysis, we identified novel missense mutations. All MTO1 mutations were predicted to be deleterious on MTO1 function. Their pathogenic role was experimentally validated in a recombinant yeast model, by assessing oxidative growth, respiratory activity, mitochondrial protein synthesis, and complex IV activity. In one case, we also demonstrated that expression of wt MTO1 could rescue the respiratory defect in mutant fibroblasts. The severity of the yeast respiratory phenotypes partly correlated with the different clinical presentations observed in MTO1 mutant patients, although the clinical outcome was highly variable in patients with the same mutation and seemed also to depend on timely start of pharmacological treatment, centered on the control of lactic acidosis by dichloroacetate. Our results indicate that MTO1 mutations are commonly associated with a presentation of hypertrophic cardiomyopathy, lactic acidosis, and MRC deficiency, and that ad hoc recombinant yeast models represent a useful system to test the pathogenic potential of uncommon variants, and provide insight into their effects on the expression of a biochemical phenotype.

Alternate JournalHum. Mutat.
Citation Key10.1002/humu.22393
PubMed ID23929671
PubMed Central IDPMC4028987
Grant List096919 / / Wellcome Trust / United Kingdom
GGP11011 / / Telethon / Italy
MR/K000608/1 / / Medical Research Council / United Kingdom
906919 / / Wellcome Trust / United Kingdom