ArticleJournal of molecular medicine (Berlin, Germany)2019
A combination of two novel VARS2 variants causes a mitochondrial disorder associated with failure to thrive and pulmonary hypertension.
Article in Journal of molecular medicine (Berlin, Germany), 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 7 papers, 1 of them a synthesis that pooled it.
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Who cites it
7 citing papers in PubMed, 1 synthesis or guideline pooled it, 7 citations in OpenAlex.
- Effectiveness of Riboflavin in Inherited Metabolic Diseases: A Systematic Review.Journal of inherited metabolic disease · 2026Pooled it
- Novel Variants in VARS2 Demonstrate the Phenotypic Variability of a Rare Mitochondriopathy That Responds to Valine Supplementation.Journal of inherited metabolic disease · 2025Article
- VARS2 Depletion Leads to Activation of the Integrated Stress Response and Disruptions in Mitochondrial Fatty Acid Oxidation.International journal of molecular sciences · 2022Article
- Transcriptome Analysis Reveals that MAPK Signaling Pathway Mediates Salt Tolerance of YMR253C ORF in Saccharomyces cerevisiae.Current microbiology · 2022Article
- 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
- Case Report and Review of the Literature: A New and a Recurrent Variant in theFrontiers in pediatrics · 2021Article
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Authors and funding
8 authors at 2 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The VARS2 gene encodes a mitochondrial valyl-transfer RNA synthetase which is used in mitochondrial translation. To date, several patients with VARS2 pathogenic variants have been described in the literature. These patients have features of lactic acidosis with encephalomyopathy. We present a case of an infant with lactic acidosis, failure to thrive, and severe primary pulmonary hypertension who was found to be a compound heterozygote for two novel VARS2 variants (c.1940C>T, p.(Thr647Met) and c.2318G>A, p.(Arg773Gln)). The patient was treated with vitamin supplements and a carbohydrate-restricted diet. The lactic acidosis and failure to thrive resolved, and he showed good growth and development. Functional studies and molecular analysis employed a yeast model system and the VAS1 gene (yeast homolog of VARS2). VAS1 genes harboring either one of two mutations corresponding to the two novel variants in the VARS2 gene, exhibited partially reduced function in haploid yeast strains. A combination of both VAS1 variant alleles in a diploid yeast cell exhibited a more significant decrease in oxidative metabolism-dependent growth and in the oxygen consumption rate (reminiscent of the patient who carries two mutant VARS2 alleles). Our results demonstrate the pathogenicity of the biallellic novel VARS2 variants. KEY MESSAGES: • A case of an infant who is a compound heterozygote for two novel VARS2 variants. • This infant displayed lactic acidosis, failure to thrive, and pulmonary hypertension. • Treatment of the patient with a carbohydrate-restricted diet resulted in good growth and development. • Studies with the homologous yeast VAS1 gene showed reduced function of corresponding single mutant in haploid yeast strains. • A combination of both VAS1 variant alleles in diploid yeast exhibited a more significant decrease in function, thereby confirming the pathogenicity of the biallellic novel VARS2 variants.
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