title: Phenotypic variability and identification of novel YARS2 mutations in YARS2 mitochondrial myopathy, lactic acidosis and sideroblastic anaemia.
abstract: BACKGROUND
  Mutations in the mitochondrial tyrosyl-tRNA synthetase (YARS2) gene have previously been identified as a cause of the tissue specific mitochondrial respiratory chain (RC) disorder, Myopathy, Lactic Acidosis, Sideroblastic Anaemia (MLASA). In this study, a cohort of patients with a mitochondrial RC disorder for who anaemia was a feature, were screened for mutations in YARS2.
  
  
  METHODS
  Twelve patients were screened for YARS2 mutations by Sanger sequencing. Clinical data were compared. Functional assays were performed to confirm the pathogenicity of the novel mutations and to investigate tissue specific effects.
  
  
  RESULTS
  PathogenicYARS2 mutations were identified in three of twelve patients screened. Two patients were found to be homozygous for the previously reported p.Phe52Leu mutation, one severely and one mildly affected. These patients had different mtDNA haplogroups which may contribute to the observed phenotypic variability. A mildly affected patient was a compound heterozygote for two novel YARS2 mutations, p.Gly191Asp and p.Arg360X. The p.Gly191Asp mutation resulted in a 38-fold loss in YARS2 catalytic efficiency and the p.Arg360X mutation did not produce a stable protein. The p.Phe52Leu and p.Gly191Asp/p.Arg360X mutations resulted in more severe RC deficiency of complexes I, III and IV in muscle cells compared to fibroblasts, but had relatively normal YARS2 protein levels. The muscle-specific RC deficiency can be related to the increased requirement for RC complexes in muscle. There was also a failure of mtDNA proliferation upon myogenesis in patient cells which may compound the RC defect. Patient muscle had increased levels of PGC1-α and TFAM suggesting mitochondrial biogenesis was activated as a potential compensatory mechanism.
  
  
  CONCLUSIONS
  In this study we have identified novel YARS2 mutations and noted marked phenotypic variability among YARS2 MLASA patients, with phenotypes ranging from mild to lethal, and we suggest that the background mtDNA haplotype may be contributing to the phenotypic variability. These findings have implications for diagnosis and prognostication of the MLASA and related phenotypes.
authors.forename: Lisa G
authors.initials: LG
authors.lastname: Riley
authors.forename: Minal J
authors.initials: MJ
authors.lastname: Menezes
authors.forename: Joëlle
authors.initials: J
authors.lastname: Rudinger-Thirion
authors.forename: Rachael
authors.initials: R
authors.lastname: Duff
authors.forename: Pascale
authors.initials: P
authors.lastname: de Lonlay
authors.forename: Agnes
authors.initials: A
authors.lastname: Rotig
authors.forename: Michel C
authors.initials: MC
authors.lastname: Tchan
authors.forename: Mark
authors.initials: M
authors.lastname: Davis
authors.forename: Sandra T
authors.initials: ST
authors.lastname: Cooper
authors.affiliation: Genetic Metabolic Disorders Research Unit, Kids Research Institute, Children's Hospital at Westmead 2145, Sydney, Australia. john.christodoulou@health.nsw.gov.au.
authors.forename: John
authors.initials: J
authors.lastname: Christodoulou
mesh_terms: D000140:Acidosis, Lactic / Q000235:genetics* / Q000378:metabolism; D000293:Adolescent; D000328:Adult; D000756:Anemia, Sideroblastic / Q000235:genetics* / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D004272:DNA, Mitochondrial / Q000235:genetics; D005260:Female; D006801:Humans; D006836:Hydro-Lyases / Q000235:genetics / Q000378:metabolism; D007223:Infant; D007231:Infant, Newborn; D017240:Mitochondrial Myopathies / Q000235:genetics* / Q000378:metabolism; D014448:Tyrosine-tRNA Ligase / Q000235:genetics* / Q000378:metabolism; D055815:Young Adult
chemical_list: D004272:DNA, Mitochondrial; D006836:Hydro-Lyases; C022479:pseudouridylate synthetase; D014448:Tyrosine-tRNA Ligase