Disrupted function and axonal distribution of mutant tyrosyl-tRNA synthetase in dominant intermediate Charcot-Marie-Tooth neuropathy

Nat Genet. 2006 Feb;38(2):197-202. doi: 10.1038/ng1727. Epub 2006 Jan 22.


Charcot-Marie-Tooth (CMT) neuropathies are common disorders of the peripheral nervous system caused by demyelination or axonal degeneration, or a combination of both features. We previously assigned the locus for autosomal dominant intermediate CMT neuropathy type C (DI-CMTC) to chromosome 1p34-p35. Here we identify two heterozygous missense mutations (G41R and E196K) and one de novo deletion (153-156delVKQV) in tyrosyl-tRNA synthetase (YARS) in three unrelated families affected with DI-CMTC. Biochemical experiments and genetic complementation in yeast show partial loss of aminoacylation activity of the mutant proteins, and mutations in YARS, or in its yeast ortholog TYS1, reduce yeast growth. YARS localizes to axonal termini in differentiating primary motor neuron and neuroblastoma cultures. This specific distribution is significantly reduced in cells expressing mutant YARS proteins. YARS is the second aminoacyl-tRNA synthetase found to be involved in CMT, thereby linking protein-synthesizing complexes with neurodegeneration.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Axons / enzymology*
  • Axons / metabolism
  • Axons / pathology
  • Biological Assay
  • COS Cells
  • Cell Line, Tumor
  • Cells, Cultured
  • Charcot-Marie-Tooth Disease / enzymology*
  • Charcot-Marie-Tooth Disease / genetics*
  • Charcot-Marie-Tooth Disease / metabolism
  • Chlorocebus aethiops
  • Genes, Dominant / genetics*
  • Genetic Complementation Test
  • Heterozygote
  • Humans
  • Mice
  • Molecular Sequence Data
  • Mutation / genetics*
  • Protein Transport
  • Recombinant Proteins
  • Saccharomyces cerevisiae / cytology
  • Saccharomyces cerevisiae / growth & development
  • Sequence Alignment
  • Tyrosine-tRNA Ligase / chemistry
  • Tyrosine-tRNA Ligase / genetics*
  • Tyrosine-tRNA Ligase / metabolism*


  • Recombinant Proteins
  • Tyrosine-tRNA Ligase

Associated data

  • RefSeq/NM_004102
  • RefSeq/NM_004814
  • RefSeq/NM_005610
  • RefSeq/NM_012392
  • RefSeq/NM_014676
  • RefSeq/NM_023009
  • RefSeq/NM_030786
  • RefSeq/NM_052896
  • RefSeq/NM_145238
  • RefSeq/NP_003680
  • RefSeq/NP_011701
  • RefSeq/NP_247363
  • RefSeq/NP_598912
  • RefSeq/NT_004511
  • SWISSPROT/P00952