Charcot-Marie-Tooth mutation in glycyl-tRNA synthetase stalls ribosomes in a pre-accommodation state and activates integrated stress response

Nucleic Acids Res. 2021 Sep 27;49(17):10007-10017. doi: 10.1093/nar/gkab730.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line
  • Charcot-Marie-Tooth Disease / genetics*
  • Eukaryotic Initiation Factor-2 / metabolism
  • Gain of Function Mutation / genetics
  • Gene Expression / genetics
  • Glycine / genetics
  • Glycine-tRNA Ligase / genetics*
  • HEK293 Cells
  • Humans
  • Peptide Chain Elongation, Translational / genetics*
  • Peptide Chain Initiation, Translational / genetics*
  • Phosphorylation
  • Protein Biosynthesis / genetics
  • RNA, Transfer, Gly / genetics
  • Ribosomes / metabolism*


  • Eukaryotic Initiation Factor-2
  • RNA, Transfer, Gly
  • Glycine-tRNA Ligase
  • Glycine