ArticleHuman molecular genetics2018
Hypermorphic and hypomorphic AARS alleles in patients with CMT2N expand clinical and molecular heterogeneities.
Article in Human molecular genetics, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers.
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Who cites it
26 citing papers in PubMed, 33 citations in OpenAlex.
- Advances in Research onGenes · 2026Review
- Modeling of Charcot-Marie-Tooth disease in zebrafish.Frontiers in molecular neuroscience · 2025Review
- Evaluation of the Role of Tanshinone I in an In Vitro System of Charcot-Marie-Tooth Disease Type 2N.International journal of molecular sciences · 2024Article
- Mechanisms and Delivery of tRNA Therapeutics.Chemical reviews · 2024Review
- AARS and CACNA1A mutations: diagnostic insights into a case report of uncommon epileptic encephalopathy phenotypes in two siblings.Frontiers in neurology · 2024Article
- DominantBrain communications · 2024Article
- A humanized yeast model reveals dominant-negative properties of neuropathy-associated alanyl-tRNA synthetase mutations.Human molecular genetics · 2023Article
- Dominant aminoacyl-tRNA synthetase disorders: lessons learned fromFrontiers in neuroscience · 2023Review
- Alanyl-tRNA Synthetase 1 Gene Variants in Hereditary Neuropathy: Genotype and Phenotype Overview.Neurology. Genetics · 2022Article
- Clinical characteristics and proteome modifications in two Charcot-Marie-Tooth families with the AARS1 Arg326Trp mutation.BMC neurology · 2022Article
- The pathophyiological role of aminoacyl-tRNA synthetases in digestive system diseases.Frontiers in physiology · 2022Review
- The uniqueness of AlaRS and its human disease connections.RNA biology · 2021Review
- Review
- tRNA overexpression rescues peripheral neuropathy caused by mutations in tRNA synthetase.Science (New York, N.Y.) · 2021Article
- Aminoacyl-tRNA synthetases in Charcot-Marie-Tooth disease: A gain or a loss?Journal of neurochemistry · 2021Review
- CMT2N-causing aminoacylation domain mutants enable Nrp1 interaction with AlaRS.Proceedings of the National Academy of Sciences of the United States of America · 2021Article
- Neuropathy-associated histidyl-tRNA synthetase variants attenuate protein synthesis in vitro and disrupt axon outgrowth in developing zebrafish.The FEBS journal · 2021Article
- Impaired Mitochondrial Mobility in Charcot-Marie-Tooth Disease.Frontiers in cell and developmental biology · 2021Article
- Associations between Neurological Diseases and Mutations in the Human Glycyl-tRNA Synthetase.Biochemistry. Biokhimiia · 2021Review
- A Yeast-Based Model for Hereditary Motor and Sensory Neuropathies: A Simple System for Complex, Heterogeneous Diseases.International journal of molecular sciences · 2020Review
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Authors and funding
17 authors at 6 institutions in 2 countries.
Funding
Abstract
Aminoacyl-tRNA synthetases (ARSs) are ubiquitously expressed enzymes implicated in several dominant and recessive disease phenotypes. The canonical function of ARSs is to couple an amino acid to a cognate transfer RNA (tRNA). We identified three novel disease-associated missense mutations in the alanyl-tRNA synthetase (AARS) gene in three families with dominant axonal Charcot-Marie-Tooth (CMT) disease. Two mutations (p.Arg326Trp and p.Glu337Lys) are located near a recurrent pathologic change in AARS, p.Arg329His. The third (p.Ser627Leu) is in the editing domain of the protein in which hitherto only mutations associated with recessive encephalopathies have been described. Yeast complementation assays demonstrated that two mutations (p.Ser627Leu and p.Arg326Trp) represent loss-of-function alleles, while the third (p.Glu337Lys) represents a hypermorphic allele. Further, aminoacylation assays confirmed that the third mutation (p.Glu337Lys) increases tRNA charging velocity. To test the effect of each mutation in the context of a vertebrate nervous system, we developed a zebrafish assay. Remarkably, all three mutations caused a pathological phenotype of neural abnormalities when expressed in zebrafish, while expression of the human wild-type messenger RNA (mRNA) did not. Our data indicate that not only functional null or hypomorphic alleles, but also hypermorphic AARS alleles can cause dominantly inherited axonal CMT disease.
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