To charge or not to charge: mechanistic insights into neuropathy-associated tRNA synthetase mutations

Curr Opin Genet Dev. 2013 Jun;23(3):302-9. doi: 10.1016/j.gde.2013.02.002. Epub 2013 Mar 4.


Aminoacyl-tRNA synthetases (ARSs) are ubiquitously expressed, essential enzymes responsible for the first step of protein translation--attaching amino acids to cognate tRNA molecules. Interestingly, ARS gene mutations have been implicated in tissue-specific human diseases, including inherited peripheral neuropathies. To date, five loci encoding an ARS have been implicated in peripheral neuropathy, and alleles at each locus show loss-of-function characteristics. The majority of the phenotypes are autosomal dominant, and each of the implicated enzymes acts as an oligomer, indicating that a dominant-negative effect should be considered. On the basis of current data, impaired tRNA charging is likely to be a central component of ARS-related neuropathy. Future efforts should focus on testing this notion and developing strategies for restoring ARS function in the peripheral nerve.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Amino Acyl-tRNA Synthetases / genetics*
  • Charcot-Marie-Tooth Disease / enzymology
  • Charcot-Marie-Tooth Disease / etiology
  • Charcot-Marie-Tooth Disease / genetics*
  • Humans
  • Mutation
  • Peripheral Nerves / enzymology
  • Peripheral Nerves / pathology
  • Peripheral Nervous System Diseases / enzymology
  • Peripheral Nervous System Diseases / etiology
  • Peripheral Nervous System Diseases / genetics*
  • Phenotype
  • Protein Biosynthesis / genetics*


  • Amino Acyl-tRNA Synthetases

Supplementary concepts

  • Inherited Peripheral Neuropathy