MTO1 mutations are associated with hypertrophic cardiomyopathy and lactic acidosis and cause respiratory chain deficiency in humans and yeast.
MTO1 mutations are associated with hypertrophic cardiomyopathy and lactic acidosis and cause respiratory chain deficiency in humans and yeast.
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DOI：
10.1002/humu.22393
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发表时间：
2013-11
期刊：
影响因子：
3.9
通讯作者：
Ghezzi, Daniele
中科院分区：
文献类型：
--
作者：
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
我们报告三个家庭表现为肥厚性心肌病，乳酸性酸中毒和线粒体呼吸链（MRC）活动的多种缺陷。通过直接测序候选基因MTO1，编码线粒体- trna修饰子1，或全外显子组测序分析，我们发现了新的错义突变。预测所有MTO1突变都对MTO1功能有害。通过评估氧化生长、呼吸活性、线粒体蛋白合成和复合物IV活性，在重组酵母模型中实验验证了它们的致病作用。在一个病例中，我们也证明了wt MTO1的表达可以挽救突变成纤维细胞的呼吸缺陷。酵母呼吸表型的严重程度与MTO1突变患者观察到的不同临床表现部分相关，尽管具有相同突变的患者的临床结果变化很大，并且似乎也取决于及时开始药物治疗，以二氯乙酸控制乳酸酸中毒为中心。我们的研究结果表明，MTO1突变通常与肥厚性心肌病、乳酸性酸中毒和MRC缺乏症的表现有关，而特别重组酵母模型代表了一个有用的系统，可以测试不常见变异的致病潜力，并提供对生化表型表达影响的见解。
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.
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影响因子：
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作者：
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