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Baruffini, E.* ; Dallabona, C.* ; Invernizzi, F.* ; Yarham, J.W.* ; Melchionda, L.* ; Blakely, E.L.* ; Lamantea, E.* ; Donnini, C.* ; Santra, S.* ; Vijayaraghavan, S.* ; Roper, H.P.* ; Burlina, A.* ; Kopajtich, R. ; Walther, A. ; Strom, T.M. ; Haack, T.B. ; Prokisch, H. ; Taylor, R.W.* ; Ferrero, I.* ; Zeviani, M.* ; Ghezzi, D.*

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

Hum. Mutat. 34, 1501-1509 (2013)
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We report three families presenting with hypertrophic cardiomyopathy, lactic acidosis, and multiple defects of mitochondrial respiratory chain 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 mitochondrial respiratory chain 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.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Mto1 ; Hypertrophic Cardiomyopathy ; Lactic Acidosis ; Mitochondrial Disorder ; Yeast; Mitochondrial Transfer-rnas ; Saccharomyces-cerevisiae ; Protein-synthesis ; Diseases ; Expression ; Anticodon ; Enzyme ; Cells ; Aminoacylation ; Biosynthesis
Language english
Publication Year 2013
HGF-reported in Year 2013
ISSN (print) / ISBN 1059-7794
e-ISSN 1098-1004
Journal Human Mutation
Quellenangaben Volume: 34, Issue: 11, Pages: 1501-1509 Article Number: , Supplement: ,
Publisher Wiley
Reviewing status Peer reviewed
Institute(s) Institute of Human Genetics (IHG)
POF-Topic(s) 30501 - Systemic Analysis of Genetic and Environmental Factors that Impact Health
Research field(s) Genetics and Epidemiology
PSP Element(s) G-500700-001
PubMed ID 23929671
DOI 10.1002/humu.22393
WOS ID WOS:000325426900009
Scopus ID 84885434357
Erfassungsdatum 2013-09-27
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