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

• Published in: Brain (London, England : 1878) England : 1878), 2010-05, Vol.133 (Pt 5), p.1460-1469
• Main Authors: Cartoni, Romain, Arnaud, Estelle, Médard, Jean-Jacques, Poirot, Olivier, Courvoisier, Delphine S, Chrast, Roman, Martinou, Jean-Claude
• Format: Article
• Language: English
• Subjects: Aging; Animals; Arginine; Axons - ultrastructure; Charcot-Marie-Tooth Disease - genetics; Charcot-Marie-Tooth Disease - pathology; Charcot-Marie-Tooth Disease - physiopathology; DNA, Complementary - metabolism; Glutamine; GTP Phosphohydrolases - genetics; 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
• ISSN: 1460-2156
• 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.