ArticleMolecular genetics & genomic medicine2019
Mutations in the mitochondrial tryptophanyl-tRNA synthetase cause growth retardation and progressive leukoencephalopathy.
Article in Molecular genetics & genomic medicine, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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Who cites it
15 citing papers in PubMed, 22 citations in OpenAlex.
- White matter disorders at the intersection of transcription, RNA processing and translation.Nature reviews. Neurology · 2026Review
- MRPS22 variants alter mitochondrial ribosome assembly in patients with leukodystrophy, movement disorder and intellectual impairment.Human molecular genetics · 2026Article
- Identification of an uncharacterized gene as a mitochondrial methionine tRNA synthetase in Caenorhabditis elegans.G3 (Bethesda, Md.) · 2026Article
- Molecular mechanisms underlying psoriasis and depression: an integrated analysis using mendelian randomization, transcriptomics, and single-cell sequencing.Frontiers in molecular medicine · 2026Article
- WARS2 -Associated Neuropsychiatric Phenotype in Childhood: A Case-Based Review.Annals of Indian Academy of Neurology · 2025Article
- Nutrient status alters developmental fates via a switch in mitochondrial homeodynamics.Nature communications · 2025Article
- Molecular pathways in mitochondrial disorders due to a defective mitochondrial protein synthesis.Frontiers in cell and developmental biology · 2024Review
- A NovelJournal of clinical neurology (Seoul, Korea) · 2023Article
- The Expanding Phenotypical Spectrum ofGenes · 2023Review
- Recessive aminoacyl-tRNA synthetase disorders: lessons learned fromFrontiers in neuroscience · 2023Review
- Epigenetic Alterations in Cryopreserved Human Spermatozoa: Suspected Potential Functional Defects.Cells · 2022Article
- Biallelic variants in KARS1 are associated with neurodevelopmental disorders and hearing loss recapitulated by the knockout zebrafish.Genetics in medicine : official journal of the American College of Medical Genetics · 2021Article
- Mitochondrial Aminoacyl-tRNA Synthetase and Disease: The Yeast Contribution for Functional Analysis of Novel Variants.International journal of molecular sciences · 2021Review
- The Power of Yeast in Modelling Human Nuclear Mutations Associated with Mitochondrial Diseases.Genes · 2021Review
- Mutations in the mitochondrial tryptophanyl-tRNA synthetase cause growth retardation and progressive leukoencephalopathy.Molecular genetics & genomic medicine · 2019Article
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Authors and funding
13 authors at 3 institutions in 3 countries.
Funding
Abstract
backgroundMutations in mitochondrial aminoacyl tRNA synthetases form a subgroup of mitochondrial disorders often only perturbing brain function by affecting mitochondrial translation. Here we report two siblings with mitochondrial disease, due to compound heterozygous mutations in the mitochondrial tryptophanyl-tRNA synthetase (WARS2) gene, presenting with severe neurological symptoms but normal mitochondrial function in skeletal muscle biopsies and cultured skin fibroblasts.
methodsWhole exome sequencing on genomic DNA samples from both subjects and their parents identified two compound heterozygous variants c.833T>G (p.Val278Gly) and c.938A>T (p.Lys313Met) in the WARS2 gene as potential disease-causing variants. We generated patient-derived neuroepithelial stem cells and modeled the disease in yeast and Drosophila melanogaster to confirm pathogenicity.
resultsBiochemical analysis of patient-derived neuroepithelial stem cells revealed a mild combined complex I and IV defect, while modeling the disease in yeast demonstrated that the reported aminoacylation defect severely affects respiration and viability. Furthermore, silencing of wild type WARS2 in Drosophila melanogaster showed that a partial defect in aminoacylation is enough to cause lethality.
conclusionsOur results establish the identified WARS2 variants as disease-causing and highlight the benefit of including human neuronal models, when investigating mutations specifically affecting the nervous system.
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