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

Cartoni, Romain ; Arnaud, Estelle ; Médard, Jean-Jacques ; Poirot, Olivier ; Courvoisier, Delphine S. ; Chrast, Roman ; Martinou, Jean-Claude

In: Brain, 2010, vol. 133, no. 5, p. 1460-1469

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    Titre
    • Expression of mitofusin 2R94Q in a transgenic mouse leads to Charcot-Marie-Tooth neuropathy type 2A
    Auteur
    • Cartoni, Romain. 1 Department of Cell Biology, University of Geneva, 30 quai Ernest-Ansermet, 1211 Genève 4, Switzerland
    • Arnaud, Estelle. 2 Department of Medical Genetics, University of Lausanne, 27 Rue du Bugnon, 1005 Lausanne, Switzerland
    • Médard, Jean-Jacques. 2 Department of Medical Genetics, University of Lausanne, 27 Rue du Bugnon, 1005 Lausanne, Switzerland
    • Poirot, Olivier. 2 Department of Medical Genetics, University of Lausanne, 27 Rue du Bugnon, 1005 Lausanne, Switzerland
    • Courvoisier, Delphine S.. 3 Division of Clinical Epidemiology, Geneva University Hospitals, University of Geneva, rue Gabrielle Perret-Gentil 4, 1211 Genève 14, Switzerland
    • Chrast, Roman. 2 Department of Medical Genetics, University of Lausanne, 27 Rue du Bugnon, 1005 Lausanne, Switzerland
    • Martinou, Jean-Claude. 1 Department of Cell Biology, University of Geneva, 30 quai Ernest-Ansermet, 1211 Genève 4, Switzerland
    Type de document
    • Postprint
    Langue
    • Inglese
    Publié dans
    • Brain, 2010, vol. 133, no. 5, p. 1460-1469. Oxford University Press
    Autre version électronique
    Identifiant OAI-PMH
    • oai:doc.rero.ch:289766
    Summary
    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 2R94Q 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 μm. 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 μm. Together these data suggest a link between an increased number of mitochondria in axons and a shift in axonal size distribution in mitofusin 2R94Q transgenic animals that may contribute to their neurological phenotype