title: Mutation of the mitochondrial tyrosyl-tRNA synthetase gene, YARS2, causes myopathy, lactic acidosis, and sideroblastic anemia--MLASA syndrome.
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.
authors.affiliation: Genetic Metabolic Disorders Research Unit, Children's Hospital at Westmead, Sydney 2145, Australia.
authors.forename: Lisa G
authors.initials: LG
authors.lastname: Riley
authors.forename: Sandra
authors.initials: S
authors.lastname: Cooper
authors.forename: Peter
authors.initials: P
authors.lastname: Hickey
authors.forename: Joëlle
authors.initials: J
authors.lastname: Rudinger-Thirion
authors.forename: Matthew
authors.initials: M
authors.lastname: McKenzie
authors.forename: Alison
authors.initials: A
authors.lastname: Compton
authors.forename: Sze Chern
authors.initials: SC
authors.lastname: Lim
authors.forename: David
authors.initials: D
authors.lastname: Thorburn
authors.forename: Michael T
authors.initials: MT
authors.lastname: Ryan
authors.forename: Richard
authors.initials: R
authors.lastname: Giegé
authors.forename: Melanie
authors.initials: M
authors.lastname: Bahlo
authors.forename: John
authors.initials: J
authors.lastname: Christodoulou
mesh_terms: D000140:Acidosis, Lactic / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D000595:Amino Acid Sequence; D000756:Anemia, Sideroblastic / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D002881:Chromosomes, Human, Pair 12 / Q000235:genetics; D003241:Consanguinity; D042967:Electron Transport Complex I / Q000502:physiology; D014450:Electron Transport Complex III / Q000502:physiology; D003576:Electron Transport Complex IV / Q000502:physiology; D005260:Female; D056726:Genetic Association Studies; D008040:Genetic Linkage; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D007223:Infant; D008297:Male; D008928:Mitochondria / Q000201:enzymology*; D008969:Molecular Sequence Data; D009135:Muscular Diseases / Q000235:genetics*; D009154:Mutation; D010375:Pedigree; D013577:Syndrome; D014448:Tyrosine-tRNA Ligase / Q000235:genetics*; D055815:Young Adult
chemical_list: D003576:Electron Transport Complex IV; D014448:Tyrosine-tRNA Ligase; D042967:Electron Transport Complex I; D014450:Electron Transport Complex III