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An active dominant mutation of glycyl-tRNA synthetase causes neuropathy in a Charcot-Marie-Tooth 2D mouse model

Academic Article
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Overview

related to degree

  • Nangle, Leslie, Ph.D. in Biology, Scripps Research 2001 - 2006

authors

  • Seburn, K. L.
  • Nangle, Leslie
  • Cox, G. A.
  • Schimmel, Paul
  • Burgess, R. W.

publication date

  • September 2006

journal

  • Neuron  Journal

abstract

  • Of the many inherited Charcot-Marie-Tooth peripheral neuropathies, type 2D (CMT2D) is caused by dominant point mutations in the gene GARS, encoding glycyl tRNA synthetase (GlyRS). Here we report a dominant mutation in Gars that causes neuropathy in the mouse. Importantly, both sensory and motor axons are affected, and the dominant phenotype is not caused by a loss of the GlyRS aminoacylation function. Mutant mice have abnormal neuromuscular junction morphology and impaired transmission, reduced nerve conduction velocities, and a loss of large-diameter peripheral axons, without defects in myelination. The mutant GlyRS enzyme retains aminoacylation activity, and a loss-of-function allele, generated by a gene-trap insertion, shows no dominant phenotype in mice. These results indicate that the CMT2D phenotype is caused not by reduction of the canonical GlyRS activity and insufficiencies in protein synthesis, but instead by novel pathogenic roles for the mutant GlyRS that specifically affect peripheral neurons.

subject areas

  • Amino Acid Sequence
  • Animals
  • Axons
  • Base Sequence
  • Charcot-Marie-Tooth Disease
  • Chromosome Mapping
  • Disease Models, Animal
  • Female
  • Genes, Dominant
  • Glycine-tRNA Ligase
  • Humans
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Microscopy, Electron, Transmission
  • Molecular Sequence Data
  • Mutation
  • Neuromuscular Junction
  • Peripheral Nervous System Diseases
  • Sciatic Nerve
  • Sequence Homology, Amino Acid
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Identity

International Standard Serial Number (ISSN)

  • 0896-6273

Digital Object Identifier (DOI)

  • 10.1016/j.neuron.2006.08.027

PubMed ID

  • 16982418
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Additional Document Info

start page

  • 715

end page

  • 726

volume

  • 51

issue

  • 6

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