Mutation of the Mitochondrial Tyrosyl-tRNA Synthetase Gene, YARS2, Causes Myopathy, Lactic Acidosis, and Sideroblastic Anemia—MLASA Syndrome
| Autor: | Peter Hickey, Joëlle Rudinger-Thirion, Richard Giegé, Alison G. Compton, Sandra T. Cooper, Lisa G. Riley, Matthew McKenzie, David R. Thorburn, Michael T. Ryan, Melanie Bahlo, Sze Chern Lim, John Christodoulou |
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| Přispěvatelé: | Genetic Metabolic Disorders Research Unit, Westmead Hospital [Sydney], Institute for Neuroscience and Muscle Research, Bioinformatics division, The Walter & Eliza Hall Institute of Medical Research, Architecture et Réactivité de l'ARN (ARN), Institut de biologie moléculaire et cellulaire (IBMC), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Department of Biochemistry, La Trobe University, Melbourne, La Trobe University [Melbourne], Murdoch Children's Research Institute (MCRI), Department of Chemistry, University of Cambridge [UK] (CAM) |
| Rok vydání: | 2010 |
| Předmět: |
Male
Genetic Linkage MESH: Sequence Homology Amino Acid Mutant Respiratory chain MESH: Amino Acid Sequence MESH: Acidosis Lactic Mitochondrion medicine.disease_cause MESH: Genotype Consanguinity Electron Transport Complex III 0302 clinical medicine Sideroblastic anemia Tyrosine-tRNA Ligase MESH: Electron Transport Complex III MESH: Child MESH: Syndrome MESH: Proteins Genetics(clinical) Child MESH: Phylogeny Genetics (clinical) MESH: Genetic Association Studies MESH: Electron Transport Complex I 0303 health sciences Mutation Syndrome MESH: Infant Mitochondria Pedigree 3. Good health MESH: Internet Mitochondrial respiratory chain Biochemistry MESH: Young Adult Child Preschool Lactic acidosis Acidosis Lactic Female Adult MESH: Mutation Adolescent Genotype MESH: Mitochondria MESH: Pedigree Molecular Sequence Data MESH: Sequence Alignment Biology Article Electron Transport Complex IV Young Adult 03 medical and health sciences Muscular Diseases MESH: Electron Transport Complex IV MESH: Evolution MESH: Tyrosine-tRNA Ligase Genetics medicine Humans TRNA aminoacylation MESH: Anemia Sideroblastic [SDV.BBM]Life Sciences [q-bio]/Biochemistry Molecular Biology Amino Acid Sequence Genetic Association Studies 030304 developmental biology MESH: Adolescent MESH: Consanguinity Chromosomes Human Pair 12 Electron Transport Complex I MESH: Humans MESH: Molecular Sequence Data MESH: Child Preschool MESH: Muscular Diseases Infant MESH: Adult medicine.disease Molecular biology MESH: Male Anemia Sideroblastic MESH: Genome-Wide Association Study MESH: Multigene Family MESH: Chromosomes Human Pair 12 MESH: Female MESH: Linkage (Genetics) 030217 neurology & neurosurgery Genome-Wide Association Study |
| Zdroj: | American Journal of Human Genetics American Journal of Human Genetics, Elsevier (Cell Press), 2010, 87 (1), pp.52-9. ⟨10.1016/j.ajhg.2010.06.001⟩ The American Journal of Human Genetics |
| ISSN: | 0002-9297 1537-6605 |
| DOI: | 10.1016/j.ajhg.2010.06.001 |
| Popis: | International audience; 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. |
| Databáze: | OpenAIRE |
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