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Metabolic impact of pathogenic variants in the mitochondrial glutamyl‐tRNA synthetase EARS2
Author(s) -
Ni Min,
Black Lauren F.,
Pan Chunxiao,
Vu Hieu,
Pei Jimin,
Ko Bookyung,
Cai Ling,
Solmonson Ashley,
Yang Chendong,
Nugent Kimberly M.,
Grishin Nick V.,
Xing Chao,
Roeder Elizabeth,
DeBerardinis Ralph J.
Publication year - 2021
Publication title -
journal of inherited metabolic disease
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.462
H-Index - 102
eISSN - 1573-2665
pISSN - 0141-8955
DOI - 10.1002/jimd.12387
Subject(s) - biology , mitochondrial dna , phenotype , metabolomics , mitochondrion , citric acid cycle , oxidative phosphorylation , mitochondrial disease , pyrimidine metabolism , lactic acidosis , purine , genotype , biochemistry , genetics , metabolism , gene , bioinformatics , enzyme
Glutamyl‐tRNA synthetase 2 (encoded by EARS2 ) is a mitochondrial aminoacyl‐tRNA synthetase required to translate the 13 subunits of the electron transport chain encoded by the mitochondrial DNA. Pathogenic EARS2 variants cause combined oxidative phosphorylation deficiency, subtype 12 (COXPD12), an autosomal recessive disorder involving lactic acidosis, intellectual disability, and other features of mitochondrial compromise. Patients with EARS2 deficiency present with variable phenotypes ranging from neonatal lethality to a mitigated disease with clinical improvement in early childhood. Here, we report a neonate homozygous for a rare pathogenic variant in EARS2 (c.949G>T; p.G317C). Metabolomics in primary fibroblasts from this patient revealed expected abnormalities in TCA cycle metabolites, as well as numerous changes in purine, pyrimidine, and fatty acid metabolism. To examine genotype‐phenotype correlations in COXPD12, we compared the metabolic impact of reconstituting these fibroblasts with wild‐type EARS2 versus four additional EARS2 variants from COXPD12 patients with varying clinical severity. Metabolomics identified a group of signature metabolites, mostly from the TCA cycle and amino acid metabolism, that discriminate between EARS2 variants causing relatively mild and severe COXPD12. Taken together, these findings indicate that metabolomics in patient‐derived fibroblasts may help establish genotype‐phenotype correlations in EARS2 deficiency and likely other mitochondrial disorders.