Expression of mitofusin 2(R94Q) in a transgenic mouse leads to Charcot-Marie-Tooth neuropathy type 2A

Brain. 2010 May;133(Pt 5):1460-9. doi: 10.1093/brain/awq082.


Charcot-Marie-Tooth disease type 2A is an autosomal dominant axonal form of peripheral neuropathy caused by mutations in the mitofusin 2 gene. Mitofusin 2 encodes a mitochondrial outer membrane protein that participates in mitochondrial fusion in mammalian cells. How mutations in this protein lead to Charcot-Marie-Tooth disease type 2A pathophysiology remains unclear. We have generated a transgenic mouse expressing either a mutated (R94Q) or wild-type form of human mitofusin 2 in neurons to evaluate whether the R94Q mutation was sufficient for inducing a Charcot-Marie-Tooth disease type 2A phenotype. Only mice expressing mitofusin 2(R94Q) developed locomotor impairments and gait defects thus mimicking the Charcot-Marie-Tooth disease type 2A neuropathy. In these animals, the number of mitochondria per axon was significantly increased in the distal part of the sciatic nerve axons with a diameter smaller than 3.5 microm. Importantly, the analysis of R94Q transgenic animals also revealed an age-related shift in the size of myelinated axons leading to an over-representation of axons smaller than 3.5 microm. Together these data suggest a link between an increased number of mitochondria in axons and a shift in axonal size distribution in mitofusin 2(R94Q) transgenic animals that may contribute to their neurological phenotype.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aging
  • Animals
  • Arginine
  • Axons / ultrastructure
  • Charcot-Marie-Tooth Disease / genetics
  • Charcot-Marie-Tooth Disease / pathology
  • Charcot-Marie-Tooth Disease / physiopathology*
  • DNA, Complementary / metabolism
  • GTP Phosphohydrolases / genetics*
  • Glutamine
  • Humans
  • Membrane Transport Proteins / genetics*
  • Mice
  • Mice, Transgenic
  • Microscopy, Electron
  • Mitochondria / ultrastructure
  • Mitochondrial Membrane Transport Proteins
  • Mitochondrial Proteins / genetics*
  • Mutation*
  • Nerve Fibers, Myelinated / pathology
  • Neurons / metabolism
  • Peripheral Nerves / ultrastructure
  • Phenotype
  • Sciatic Nerve / pathology


  • DNA, Complementary
  • Membrane Transport Proteins
  • Mitochondrial Membrane Transport Proteins
  • Mitochondrial Proteins
  • Glutamine
  • Arginine
  • GTP Phosphohydrolases
  • Mfn1 protein, human