ArticleHuman molecular genetics2023
Histidine supplementation can escalate or rescue HARS deficiency in a Charcot-Marie-Tooth disease model.
Article in Human molecular genetics, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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Who cites it
20 citing papers in PubMed, 18 citations in OpenAlex.
- Therapeutic rescue of pathogenic asparaginyl-tRNA synthetase alleles.Molecular therapy. Nucleic acids · 2026Article
- Tyrosine Supplementation Rescues a Growth Defect in a HumanizedInternational journal of molecular sciences · 2026Article
- Leucyl tRNA synthetase ameliorates cholestatic liver injury by inhibiting integrated stress response in mice.Scientific reports · 2026Article
- Aminoacyl-tRNA Synthetases: Variant Classification, Functional Assays, and Emerging Therapeutic Strategies.Journal of inherited metabolic disease · 2026Review
- Inhibition of the integrated stress response rescues a histidyl-tRNA synthetase variant associated with Charcot-Marie-Tooth disease.NAR molecular medicine · 2026Article
- Novel Variants in VARS2 Demonstrate the Phenotypic Variability of a Rare Mitochondriopathy That Responds to Valine Supplementation.Journal of inherited metabolic disease · 2025Article
- Global partnerships in rare disease research.Disease models & mechanisms · 2025Article
- Transfer RNA and small molecule therapeutics for aminoacyl-tRNA synthetase diseases.The FEBS journal · 2025Review
- Yeast models for Charcot-Marie-Tooth disease-causing aminoacyl-tRNA synthetase alleles reveal the cellular basis of disease.IUBMB life · 2025Review
- Modeling of Charcot-Marie-Tooth disease in zebrafish.Frontiers in molecular neuroscience · 2025Review
- Aminoacyl-tRNA synthetase defects in neurological diseases.IUBMB life · 2025Review
- Current approaches for Usher syndrome disease models and developing therapies.Frontiers in cell and developmental biology · 2025Review
- Transfer RNA supplementation rescues HARS deficiency in a humanized yeast model of Charcot-Marie-Tooth disease.Nucleic acids research · 2024Article
- Characterization of a novel heterozygous variant in the histidyl-tRNA synthetase gene associated with Charcot-Marie-Tooth disease type 2W.IUBMB life · 2024Article
- Gcn2 structurally mimics and functionally repurposes the HisRS enzyme for the integrated stress response.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Mechanisms and Delivery of tRNA Therapeutics.Chemical reviews · 2024Review
- Interplay between mistranslation and oxidative stress inArhiv za higijenu rada i toksikologiju · 2024Article
- Coordination between aminoacylation and editing to protect against proteotoxicity.Nucleic acids research · 2023Article
- Genetic Interaction of tRNA-Dependent Mistranslation with Fused in Sarcoma Protein Aggregates.Genes · 2023Article
- Towards a Cure for HARS Disease.Genes · 2023Review
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Authors and funding
8 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Aminoacyl-tRNA synthetases are essential enzymes responsible for charging amino acids onto cognate tRNAs during protein synthesis. In histidyl-tRNA synthetase (HARS), autosomal dominant mutations V133F, V155G, Y330C and S356N in the HARS catalytic domain cause Charcot-Marie-Tooth disease type 2 W (CMT2W), while tRNA-binding domain mutation Y454S causes recessive Usher syndrome type IIIB. In a yeast model, all human HARS variants complemented a genomic deletion of the yeast ortholog HTS1 at high expression levels. CMT2W associated mutations, but not Y454S, resulted in reduced growth. We show mistranslation of histidine to glutamine and threonine in V155G and S356N but not Y330C mutants in yeast. Mistranslating V155G and S356N mutants lead to accumulation of insoluble proteins, which was rescued by histidine. Mutants V133F and Y330C showed the most significant growth defect and decreased HARS abundance in cells. Here, histidine supplementation led to insoluble protein aggregation and further reduced viability, indicating histidine toxicity associated with these mutants. V133F proteins displayed reduced thermal stability in vitro, which was rescued by tRNA. Our data will inform future treatment options for HARS patients, where histidine supplementation may either have a toxic or compensating effect depending on the nature of the causative HARS variant.
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