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A novel mutation in YARS2 causes myopathy with lactic acidosis and sideroblastic anemia

2012; Wiley; Volume: 33; Issue: 8 Linguagem: Inglês

10.1002/humu.22098

1098-1004

Florin Sasarman, Tamiko Nishimura, Isabelle Thiffault, Eric A. Shoubridge,

Metabolism and Genetic Disorders

Human MutationVolume 33, Issue 8 p. 1201-1206 Research Article A novel mutation in YARS2 causes myopathy with lactic acidosis and sideroblastic anemia† Florin Sasarman, Florin Sasarman Montreal Neurological Institute, McGill University, Montreal, Canada Department of Human Genetics, McGill University, Montreal, CanadaSearch for more papers by this authorTamiko Nishimura, Tamiko Nishimura Montreal Neurological Institute, McGill University, Montreal, Canada Department of Human Genetics, McGill University, Montreal, CanadaSearch for more papers by this authorIsabelle Thiffault, Isabelle Thiffault Montreal Neurological Institute, McGill University, Montreal, Canada Department of Human Genetics, McGill University, Montreal, CanadaSearch for more papers by this authorEric A. Shoubridge, Corresponding Author Eric A. Shoubridge [email protected] Montreal Neurological Institute, McGill University, Montreal, Canada Department of Human Genetics, McGill University, Montreal, CanadaMontreal Neurological Institute, 3801 University Street, Montreal, Quebec H3A 2B4, Canada.Search for more papers by this author Florin Sasarman, Florin Sasarman Montreal Neurological Institute, McGill University, Montreal, Canada Department of Human Genetics, McGill University, Montreal, CanadaSearch for more papers by this authorTamiko Nishimura, Tamiko Nishimura Montreal Neurological Institute, McGill University, Montreal, Canada Department of Human Genetics, McGill University, Montreal, CanadaSearch for more papers by this authorIsabelle Thiffault, Isabelle Thiffault Montreal Neurological Institute, McGill University, Montreal, Canada Department of Human Genetics, McGill University, Montreal, CanadaSearch for more papers by this authorEric A. Shoubridge, Corresponding Author Eric A. Shoubridge [email protected] Montreal Neurological Institute, McGill University, Montreal, Canada Department of Human Genetics, McGill University, Montreal, CanadaMontreal Neurological Institute, 3801 University Street, Montreal, Quebec H3A 2B4, Canada.Search for more papers by this author First published: 13 April 2012 https://doi.org/10.1002/humu.22098Citations: 38 † Communicated by Jan P. Kraus Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Abstract Mutations in the mitochondrial aminoacyl-tRNA synthetases (ARSs) are associated with a strikingly broad range of clinical phenotypes, the molecular basis for which remains obscure. Here, we report a novel missense mutation (c.137G>A, p.Gly46Asp) in the catalytic domain of YARS2, which codes for the mitochondrial tyrosyl-tRNA synthetase, in a subject with myopathy, lactic acidosis, and sideroblastic anemia (MLASA). YARS2 was undetectable by immunoblot analysis in subject myoblasts, resulting in a generalized mitochondrial translation defect. Retroviral expression of a wild-type YARS2 complementary DNA completely rescued the translation defect. We previously demonstrated that the respiratory chain defect in this subject was only present in fully differentiated muscle, and we show here that this likely reflects an increased requirement for YARS2 as muscle cells differentiate. An additional, heterozygous mutation was detected in TRMU/MTU1, a gene encoding the mitochondrial 2-thiouridylase. Although subject myoblasts and myotubes contained half the normal levels of TRMU, thiolation of mitochondrial tRNAs was normal. YARS2 eluted as part of high-molecular-weight complexes of ∼250 kDa and 1 MDa by gel filtration. This study confirms mutations in YARS2 as a cause of MLASA and shows that, like some of the cytoplasmic ARSs, mitochondrial ARSs occur in high-molecular-weight complexes. Hum Mutat 33:1201–1206, 2012. © 2012 Wiley Periodicals, Inc. Citing Literature Volume33, Issue8August 2012Pages 1201-1206 RelatedInformation