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A novel mutation in YARS2 causes myopathy with lactic acidosis and sideroblastic anemia
Author(s) -
Sasarman Florin,
Nishimura Tamiko,
Thiffault Isabelle,
Shoubridge Eric A.
Publication year - 2012
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.22098
Subject(s) - biology , lactic acidosis , sideroblastic anemia , missense mutation , mutation , mitochondrial dna , mitochondrial disease , microbiology and biotechnology , mitochondrial myopathy , myopathy , mitochondrion , genetics , compound heterozygosity , phenotype , gene , biochemistry
Mutations in the mitochondrial aminoacyl‐tRNA synthetases (ARSs) are associated with a strikingly broad range of clinical phenotypes, the molecular basis for which remains obscure. Here, we report a novel missense mutation (c.137G>A, p.Gly46Asp) in the catalytic domain of YARS2 , which codes for the mitochondrial tyrosyl‐tRNA synthetase, in a subject with myopathy, lactic acidosis, and sideroblastic anemia (MLASA). YARS2 was undetectable by immunoblot analysis in subject myoblasts, resulting in a generalized mitochondrial translation defect. Retroviral expression of a wild‐type YARS2 complementary DNA completely rescued the translation defect. We previously demonstrated that the respiratory chain defect in this subject was only present in fully differentiated muscle, and we show here that this likely reflects an increased requirement for YARS2 as muscle cells differentiate. An additional, heterozygous mutation was detected in TRMU / MTU1 , a gene encoding the mitochondrial 2‐thiouridylase. Although subject myoblasts and myotubes contained half the normal levels of TRMU, thiolation of mitochondrial tRNAs was normal. YARS2 eluted as part of high‐molecular‐weight complexes of ∼250 kDa and 1 MDa by gel filtration. This study confirms mutations in YARS2 as a cause of MLASA and shows that, like some of the cytoplasmic ARSs, mitochondrial ARSs occur in high‐molecular‐weight complexes. Hum Mutat 33:1201–1206, 2012. © 2012 Wiley Periodicals, Inc.