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MTO 1 Mutations are Associated with Hypertrophic Cardiomyopathy and Lactic Acidosis and Cause Respiratory Chain Deficiency in Humans and Yeast
Author(s) -
Baruffini Enrico,
Dallabona Cristina,
Invernizzi Federica,
Yarham John W.,
Melchionda Laura,
Blakely Emma L.,
Lamantea Eleonora,
Donnini Claudia,
Santra Saikat,
Vijayaraghavan Suresh,
Roper Helen P.,
Burlina Alberto,
Kopajtich Robert,
Walther Anett,
Strom Tim M.,
Haack Tobias B.,
Prokisch Holger,
Taylor Robert W.,
Ferrero Ileana,
Zeviani Massimo,
Ghezzi Daniele
Publication year - 2013
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.22393
Subject(s) - biology , missense mutation , lactic acidosis , exome sequencing , mutation , respiratory chain , genetics , mitochondrion , gene , endocrinology
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 MTO 1 , encoding the mitochondrial‐t RNA modifier 1, or whole exome sequencing analysis, we identified novel missense mutations. All MTO 1 mutations were predicted to be deleterious on MTO 1 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 MTO 1 could rescue the respiratory defect in mutant fibroblasts. The severity of the yeast respiratory phenotypes partly correlated with the different clinical presentations observed in MTO 1 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 MTO 1 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.