Phenotypic variability and identification of novel YARS2 mutations in YARS2 mitochondrial myopathy, lactic acidosis and sideroblastic anaemia

Orphanet Journal of Rare Diseases

John Christodoulou⁵  Sandra T Cooper¹  Mark Davis⁷  Michel C Tchan⁴  Agnes Rotig³  Pascale de Lonlay³  Rachael Duff⁶  Joëlle Rudinger-Thirion²  Minal J Menezes⁸  Lisa G Riley⁸ 

[1] Institute for Neuroscience and Muscle Research, Kids Research Institute, Children’s Hospital at Westmead 2145, Sydney, Australia;Architecture et Réactivité de l’ARN, Université de Strasbourg, CNRS, IBMC, Strasbourg 67084, France;Université Paris Descartes and INSERM U781, Hôpital Necker-Enfants Malades, Paris 75015, France;Department of Genetic Medicine, Westmead Hospital, Sydney, Australia;Discipline of Genetic Medicine, Sydney Medical School, University of Sydney 2006, Sydney, Australia;Centre for Medical Research, University of Western Australia and Western Australian Institute for Medical Research, Perth, Western Australia 6009, Australia;Diagnostic Genomics, PathWest Laboratory Medicine, QEII Medical Centre, Nedlands, WA 6009, Australia;Discipline of Paediatrics & Child Health, University of Sydney 2006, Sydney, Australia

关键词: Mutation;    Inborn error of metabolism;    Lactic acidaemia;    Muscle diseases;    Mitochondrial myopathies;    Aminoacyl tRNA-synthetase;    Myopathy with lactic acidosis and sideroblastic anemia;    Mitochondrial respiratory chain;   

Others  :  863354
DOI  :  10.1186/1750-1172-8-193

 received in 2013-08-16, accepted in 2013-12-13,  发布年份 2013

【 摘 要 】

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.

Conclusion

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.

【 授权许可】

   
2013 Riley et al.; licensee BioMed Central Ltd.

【 图 表 】

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