Reversal of neuropathy phenotypes in conditional mouse model of Charcot-Marie-Tooth disease type 2E

Hum Mol Genet. 2010 Jul 1;19(13):2616-29. doi: 10.1093/hmg/ddq149. Epub 2010 Apr 26.


Mutations in the gene encoding for the neurofilament light subunit (NF-L) are responsible for Charcot-Marie-Tooth (CMT) neuropathy type 2E. To address whether CMT2E disease is potentially reversible, we generated a mouse model with conditional doxycycline-responsive gene system that allows repression of mutant hNF-LP22S transgene expression in adult neurons. The hNF-LP22S;tTa transgenic (tg) mice recapitulated key features of CMT2E disease, including aberrant hindlimb posture, motor deficits, hypertrophy of muscle fibres and loss of muscle innervation without neuronal loss. Remarkably, a 3-month treatment of hNF-LP22S;tTa mice with doxycycline after onset of disease efficiently down-regulated expression of hNF-LP22S and it caused reversal of CMT neurological phenotypes with restoration of muscle innervation and of neurofilament protein distribution along the sciatic nerve. These data suggest that therapeutic approaches aimed at abolishing expression or neutralizing hNF-L mutants might not only halt the progress of CMT2E disease, but also revert the disabilities.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Genetically Modified
  • Charcot-Marie-Tooth Disease* / genetics
  • Charcot-Marie-Tooth Disease* / pathology
  • Charcot-Marie-Tooth Disease* / therapy
  • Disease Models, Animal
  • Down-Regulation
  • Mice
  • Mice, Inbred Strains
  • Muscles / innervation
  • Muscles / pathology
  • Mutant Proteins / antagonists & inhibitors
  • Mutant Proteins / metabolism
  • Neurofilament Proteins / genetics*
  • Neurofilament Proteins / metabolism
  • Sciatic Nerve / pathology


  • Mutant Proteins
  • Neurofilament Proteins