Baruffini, Enrico and Dallabona, Cristina and Invernizzi, Federica and Yarham, John W and Melchionda, Laura and Blakely, Emma L and Lamantea, Eleonora and Donnini, Claudia and Santra, Saikat and Vijayaraghavan, Suresh and Roper, Helen P and Burlina, Alberto and Kopajtich, Robert and Walther, Anett and Strom, Tim M and Haack, Tobias B and Prokisch, Holger and Taylor, Robert W and Ferrero, Ileana and Zeviani, Massimo and Ghezzi, Daniele (2013) MTO1 mutations are associated with hypertrophic cardiomyopathy and lactic acidosis and cause respiratory chain deficiency in humans and yeast. Human mutation, 34 (11). pp. 1501-9. ISSN 1098-1004. This article is accessible to all HEFT staff and students via NHS Evidence www.evidence.nhs.uk by using their HEFT Athens login IDsFull text not available from this repository.
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.
|Additional Information:||This article is accessible to all HEFT staff and students via NHS Evidence www.evidence.nhs.uk by using their HEFT Athens login IDs|
|Subjects:||QC-QM General sciences|
|Depositing User:||Sophie Rollason|
|Date Deposited:||11 Jun 2014 13:44|
|Last Modified:||11 Jun 2014 13:44|
Actions (login required)