ArticleHuman mutation2018
Substrate interaction defects in histidyl-tRNA synthetase linked to dominant axonal peripheral neuropathy.
Article in Human mutation, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers.
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Who cites it
27 citing papers in PubMed, 33 citations in OpenAlex.
- Yeast models for Charcot-Marie-Tooth disease-causing aminoacyl-tRNA synthetase alleles reveal the cellular basis of disease.IUBMB life · 2025Review
- Simultaneous determination of cytosolic aminoacyl-tRNA synthetase activities by LC-MS/MS.Nucleic acids research · 2024Article
- Boosting BDNF in muscle rescues impaired axonal transport in a mouse model of DI-CMTC peripheral neuropathy.bioRxiv : the preprint server for biology · 2024Article
- Genetic Heterogeneity Underlying Phenotypes with Early-Onset Cerebellar Atrophy.International journal of molecular sciences · 2023Article
- A humanized yeast model reveals dominant-negative properties of neuropathy-associated alanyl-tRNA synthetase mutations.Human molecular genetics · 2023Article
- Histidine supplementation can escalate or rescue HARS deficiency in a Charcot-Marie-Tooth disease model.Human molecular genetics · 2023Article
- Towards a Cure for HARS Disease.Genes · 2023Review
- Dominant aminoacyl-tRNA synthetase disorders: lessons learned fromFrontiers in neuroscience · 2023Review
- Retinal Phenotype of Patients with CLRN1-Associated Usher 3A Syndrome in French Light4Deaf Cohort.Investigative ophthalmology & visual science · 2022Article
- Review
- tRNA overexpression rescues peripheral neuropathy caused by mutations in tRNA synthetase.Science (New York, N.Y.) · 2021Article
- Early and late manifestations of neuropathy due to HSPB1 mutation in the Jewish Iranian population.Annals of clinical and translational neurology · 2021Article
- Aminoacyl-tRNA synthetases in Charcot-Marie-Tooth disease: A gain or a loss?Journal of neurochemistry · 2021Review
- Associations between Neurological Diseases and Mutations in the Human Glycyl-tRNA Synthetase.Biochemistry. Biokhimiia · 2021Review
- Neuropathy-associated histidyl-tRNA synthetase variants attenuate protein synthesis in vitro and disrupt axon outgrowth in developing zebrafish.The FEBS journal · 2021Article
- Evidence for a dominant-negative mechanism in HARS1-mediated peripheral neuropathy.The FEBS journal · 2021Article
- A variant of the geneAdvances in laboratory medicine · 2020Article
- Atypical and ultra-rare Usher syndrome: a review.Ophthalmic genetics · 2020Review
- Bi-allelic mutations in HARS1 severely impair histidyl-tRNA synthetase expression and enzymatic activity causing a novel multisystem ataxic syndrome.Human mutation · 2020Article
- YARS as an oncogenic protein that promotes gastric cancer progression through activating PI3K-Akt signaling.Journal of cancer research and clinical oncology · 2020Article
Corrections and comments
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Authors and funding
19 authors at 10 institutions in 4 countries.
Funding
Abstract
Histidyl-tRNA synthetase (HARS) ligates histidine to cognate tRNA molecules, which is required for protein translation. Mutations in HARS cause the dominant axonal peripheral neuropathy Charcot-Marie-Tooth disease type 2W (CMT2W); however, the precise molecular mechanism remains undefined. Here, we investigated three HARS missense mutations associated with CMT2W (p.Tyr330Cys, p.Ser356Asn, and p.Val155Gly). The three mutations localize to the HARS catalytic domain and failed to complement deletion of the yeast ortholog (HTS1). Enzyme kinetics, differential scanning fluorimetry (DSF), and analytical ultracentrifugation (AUC) were employed to assess the effect of these substitutions on primary aminoacylation function and overall dimeric structure. Notably, the p.Tyr330Cys, p.Ser356Asn, and p.Val155Gly HARS substitutions all led to reduced aminoacylation, providing a direct connection between CMT2W-linked HARS mutations and loss of canonical ARS function. While DSF assays revealed that only one of the variants (p.Val155Gly) was less thermally stable relative to wild-type, all three HARS mutants formed stable dimers, as measured by AUC. Our work represents the first biochemical analysis of CMT-associated HARS mutations and underscores how loss of the primary aminoacylation function can contribute to disease pathology.
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Registered trials
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