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

Content Provider	Springer Nature : BioMed Central
Author	Riley, Lisa G Menezes, Minal J Rudinger-Thirion, Joëlle Duff, Rachael de Lonlay, Pascale Rotig, Agnes Tchan, Michel C Davis, Mark Cooper, Sandra T Christodoulou, John
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. 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.
Related Links	https://ojrd.biomedcentral.com/counter/pdf/10.1186/1750-1172-8-193.pdf
Ending Page	11
Page Count	11
Starting Page	1
File Format	HTM / HTML
ISSN	17501172
DOI	10.1186/1750-1172-8-193
Journal	Orphanet Journal of Rare Diseases
Issue Number	1
Volume Number	8
Language	English
Publisher	BioMed Central
Publisher Date	2013-12-17
Access Restriction	Open
Subject Keyword	Medicine Public Health Pharmacology Toxicology Human Genetics Mitochondrial respiratory chain Myopathy with lactic acidosis and sideroblastic anemia Aminoacyl tRNA-synthetase Mitochondrial myopathies Muscle diseases Lactic acidaemia Inborn error of metabolism Mutation Medicine/Public Health Pharmacology/Toxicology
Content Type	Text
Resource Type	Article
Subject	Pharmacology (medical) Genetics (clinical)
Journal Impact Factor	3.4/2023
5-Year Journal Impact Factor	3.9/2023

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

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