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Mutation of the Mitochondrial Tyrosyl-tRNA Synthetase Gene, YARS2, Causes Myopathy, Lactic Acidosis, and Sideroblastic Anemia—MLASA Syndrome |
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| Authors: | Lisa G. Riley Peter Hickey Matthew McKenzie Sze Chern Lim David Thorburn Michael T. Ryan Melanie Bahlo |
| Affiliation: | 1 Genetic Metabolic Disorders Research Unit, Children's Hospital at Westmead, Sydney 2145, Australia 2 Institute for Neuroscience and Muscle Research, Children's Hospital at Westmead, Sydney 2145, Australia 3 Discipline of Paediatrics & Child Health, University of Sydney, Sydney 2006, Australia 4 Bioinformatics Division, The Walter & Eliza Hall Institute of Medical Research, Melbourne 3050, Australia 5 Architecture et Réactivité de l'ARN, Université de Strasbourg, CNRS, IBMC, 67000 Strasbourg, France 6 Department of Biochemistry, La Trobe University, Melbourne 3086, Australia 7 Murdoch Childrens Research Institute and Genetic Health Services Victoria, Royal Children's Hospital, Melbourne 3052, Australia 8 Department of Paediatrics, University of Melbourne, Melbourne 3010, Australia 9 Discipline of Genetic Medicine, University of Sydney, Sydney 2006, Australia |
| Abstract: | Mitochondrial respiratory chain disorders are a heterogeneous group of disorders in which the underlying genetic defect is often unknown. We have identified a pathogenic mutation (c.156C>G [p.F52L]) in YARS2, located at chromosome 12p11.21, by using genome-wide SNP-based homozygosity analysis of a family with affected members displaying myopathy, lactic acidosis, and sideroblastic anemia (MLASA). We subsequently identified the same mutation in another unrelated MLASA patient. The YARS2 gene product, mitochondrial tyrosyl-tRNA synthetase (YARS2), was present at lower levels in skeletal muscle whereas fibroblasts were relatively normal. Complex I, III, and IV were dysfunctional as indicated by enzyme analysis, immunoblotting, and immunohistochemistry. A mitochondrial protein-synthesis assay showed reduced levels of respiratory chain subunits in myotubes generated from patient cell lines. A tRNA aminoacylation assay revealed that mutant YARS2 was still active; however, enzyme kinetics were abnormal compared to the wild-type protein. We propose that the reduced aminoacylation activity of mutant YARS2 enzyme leads to decreased mitochondrial protein synthesis, resulting in mitochondrial respiratory chain dysfunction. MLASA has previously been associated with PUS1 mutations; hence, the YARS2 mutation reported here is an alternative cause of MLASA. |
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