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MTO1 Mutations are Associated with Hypertrophic Cardiomyopathy and Lactic Acidosis and Cause Respiratory Chain Deficiency in Humans and Yeast

Lookup NU author(s): Dr Emma Watson, Professor Robert Taylor


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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.

Publication metadata

Author(s): Baruffini 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

Publication type: Article

Publication status: Published

Journal: Human Mutation

Year: 2013

Volume: 34

Issue: 11

Pages: 1501-1509

Print publication date: 01/11/2013

Online publication date: 17/09/2013

Acceptance date: 19/07/2013

ISSN (print): 1059-7794

ISSN (electronic): 1098-1004

Publisher: John Wiley & Sons, Inc.


DOI: 10.1002/humu.22393


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Funder referenceFunder name
Pierfranco and Luisa Mariani Foundation of Italy
Italian Association of Mitochondrial Disease Patients and Families (Mitocon)
Medical Research Council (UK)
UK NHS Specialist Commissioners
01GM0867German Network for Mitochondrial Disorders (mitoNET)
01GM1113CGerman Network for Mitochondrial Disorders (mitoNET)
01GM1207E-rare Grant GenoMit
0315494AGerman Federal Ministry of Education and Research (BMBF)
906919Wellcome Trust
FWF I 920-B13E-rare Grant GenoMit
GPP10005Fondazione Telethon
GR2010-2316392Italian Ministry of Health
GGP11011Fondazione Telethon
JTC2011E-rare Grant GenoMit