Mutations of the Mitochondrial-tRNA Modifier MTO1 Cause Hypertrophic Cardiomyopathy and Lactic Acidosis

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• 作者：Daniele Ghezzi¹ ; ⁷ ; Enrico Baruffini² ; ⁷ ; Tobias  ; B. Haack³ ; ⁴ ; Federica Invernizzi¹ ; Laura Melchionda¹ ; Cristina Dallabona² ; Tim  ; M. Strom³ ; ⁴ ; Rossella Parini⁵ ; Alberto  ; B. Burlina⁶ ; Thomas Meitinger³ ; ⁴ ; Holger Prokisch³ ; ⁴ ; Ileana Ferrero² ; Massimo Zeviani¹ ; ^{zeviani@istituto-besta.it}
• 刊名：The American Journal of Human Genetics
• 出版年：2012
• 出版时间：8 June, 2012
• 年：2012
• 卷：90
• 期：6
• 页码：1079-1087
• 全文大小：766 K

文摘

Dysfunction of mitochondrial respiration is an increasingly recognized cause of isolated hypertrophic cardiomyopathy. To gain insight into the genetic origin of this condition, we used next-generation exome sequencing to identify mutations in MTO1, which encodes mitochondrial translation optimization 1. Two affected siblings carried a maternal c.1858dup (p.Arg620Lysfs^{?/sup>8) frameshift and a paternal c.1282G>A (p.Ala428Thr) missense mutation. A third unrelated individual was homozygous for the latter change. In both humans and yeast, MTO1 increases the accuracy and efficiency of mtDNA translation by catalyzing the 5-carboxymethylaminomethylation of the wobble uridine base in three mitochondrial tRNAs (mt-tRNAs). Accordingly, mutant muscle and fibroblasts showed variably combined reduction in mtDNA-dependent respiratory chain activities. Reduced respiration in mutant cells was corrected by expressing a wild-type MTO1 cDNA. Conversely, defective respiration of a yeast mto1¦¤ strain failed to be corrected by an Mto1Pro622?/sup> variant, equivalent to human MTO1Arg620Lysfs?, whereas incomplete correction was achieved by an Mto1Ala431Thr variant, corresponding to human MTO1Ala428Thr. The respiratory yeast phenotype was dramatically worsened in stress conditions and in the presence of a paromomycin-resistant (PR) mitochondrial rRNA mutation. Lastly, in?vivo mtDNA translation was impaired in the mutant yeast strains.}