Metabolic impact of pathogenic variants in the mitochondrial glutamyl‐tRNA synthetase EARS2
| Autor: | Lauren Friedrich, Hieu Sy Vu, Chao Xing, Kimberly M. Nugent, Ralph J. DeBerardinis, Nick V. Grishin, Chendong Yang, Elizabeth Roeder, Jimin Pei, Ashley Solmonson, Chunxiao Pan, Bookyung Ko, Min Ni, Ling Cai |
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| Rok vydání: | 2021 |
| Předmět: |
Male
Purine Mitochondrial DNA Mitochondrial disease Oxidative phosphorylation Biology Mitochondrion Article Amino Acyl-tRNA Synthetases 03 medical and health sciences chemistry.chemical_compound Leukoencephalopathies Intellectual Disability Genetics medicine Humans Child Genetic Association Studies Genetics (clinical) 030304 developmental biology 0303 health sciences Fatty acid metabolism 030305 genetics & heredity Infant Newborn Genetic Variation Infant medicine.disease Mitochondria Citric acid cycle Glutamate-tRNA Ligase chemistry Child Preschool Lactic acidosis Mutation Acidosis Lactic Female Metabolism Inborn Errors |
| Zdroj: | J Inherit Metab Dis |
| ISSN: | 1573-2665 0141-8955 |
| Popis: | 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 vs. 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. This article is protected by copyright. All rights reserved. |
| Databáze: | OpenAIRE |
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