ArticleNucleic acids research2021
Charcot-Marie-Tooth mutation in glycyl-tRNA synthetase stalls ribosomes in a pre-accommodation state and activates integrated stress response.
Article in Nucleic acids research, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 33 papers.
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33 citing papers in PubMed, 38 citations in OpenAlex.
- Review
- Therapeutic rescue of pathogenic asparaginyl-tRNA synthetase alleles.Molecular therapy. Nucleic acids · 2026Article
- Multi-omics analysis reveals the mechanism of enhanced GABA production in Lactiplantibacillus plantarum JY7 under acoustic and thermal coupling.Ultrasonics sonochemistry · 2026Article
- Human aminoacyl-tRNA synthetases as integrators of translation and cell signalling networks.Nature reviews. Molecular cell biology · 2026Review
- Junctions in Jeopardy: the neuromuscular junction is a selective pathological target in Charcot-Marie-Tooth disease.Mammalian genome : official journal of the International Mammalian Genome Society · 2026Review
- A class of deep intronicmedRxiv : the preprint server for health sciences · 2026Article
- Mistranslation from an endogenous tRNA variant in human pan-genome cell lines.Nucleic acids research · 2026Article
- Genetic commonalities between rare subtypes of ALS and CMT: insights into molecular mechanisms of neurodegeneration.Amino acids · 2026Review
- Inhibition of the integrated stress response rescues a histidyl-tRNA synthetase variant associated with Charcot-Marie-Tooth disease.NAR molecular medicine · 2026Article
- Axonal Eif5a hypusination controls local translation and mitigates defects in FUS-ALS.Nature neuroscience · 2026Article
- Systematic analysis of noncanonical ribosomal protein paralogs does not provide evidence for specialized functions inProceedings of the National Academy of Sciences of the United States of America · 2025Article
- Biallelic Variants in the DARS2 Gene as a Novel Cause of Axonal Charcot-Marie-Tooth Disease.Annals of neurology · 2025Article
- Article
- Interpreting ribosome dynamics during mRNA translation.The Journal of biological chemistry · 2025Review
- Lysyl-tRNA synthetase orchestrates translation and hormone signaling during reproduction in Aedes aegypti mosquitoes.Communications biology · 2025Article
- Serine mistranslation induces the integrated stress response through the P stalk.The Journal of biological chemistry · 2025Article
- Isoleucine-to-valine substitutions support cellular physiology during isoleucine deprivation.Nucleic acids research · 2025Article
- Analysis of the mechanism of skeletal muscle atrophy from the pathway of decreased protein synthesis.Frontiers in physiology · 2025Review
- Transfer RNA supplementation rescues HARS deficiency in a humanized yeast model of Charcot-Marie-Tooth disease.Nucleic acids research · 2024Article
- IGHMBP2 deletion suppresses translation and activates the integrated stress response.Life science alliance · 2024Article
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4 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Toxic gain-of-function mutations in aminoacyl-tRNA synthetases cause a degeneration of peripheral motor and sensory axons, known as Charcot-Marie-Tooth (CMT) disease. While these mutations do not disrupt overall aminoacylation activity, they interfere with translation via an unknown mechanism. Here, we dissect the mechanism of function of CMT mutant glycyl-tRNA synthetase (CMT-GARS), using high-resolution ribosome profiling and reporter assays. We find that CMT-GARS mutants deplete the pool of glycyl-tRNAGly available for translation and inhibit the first stage of elongation, the accommodation of glycyl-tRNA into the ribosomal A-site, which causes ribosomes to pause at glycine codons. Moreover, ribosome pausing activates a secondary repression mechanism at the level of translation initiation, by inducing the phosphorylation of the alpha subunit of eIF2 and the integrated stress response. Thus, CMT-GARS mutant triggers translational repression via two interconnected mechanisms, affecting both elongation and initiation of translation.
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