The “CMT Rat”: Peripheral Neuropathy and Dysmyelination Caused by Transgenic Overexpression of PMP22

Authors

  • STEPHAN NIEMANN,

    1. Zentrum für Molekulare Biologie (ZMBH), University of Heidelberg, D-69120 Heidelberg, Germany
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  • MICHAEL W. SEREDA,

    1. Zentrum für Molekulare Biologie (ZMBH), University of Heidelberg, D-69120 Heidelberg, Germany
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  • MORITZ ROSSNER,

    1. Zentrum für Molekulare Biologie (ZMBH), University of Heidelberg, D-69120 Heidelberg, Germany
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  • HELEN STEWART,

    1. Zentrum für Molekulare Biologie (ZMBH), University of Heidelberg, D-69120 Heidelberg, Germany
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  • UELI SUTER,

    1. Institute of Cell Biology, Department of Biology, Swiss Federal Institute of Technology, ETH-Hoenggerberg, CH-8093 Zürich, Switzerland
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  • HANS-MICHAEL MEINCK,

    1. Department of Neurology, University of Heidelberg, D-69120 Heidelberg, Germany
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  • IAN R. GRIFFITHS,

    1. Applied Neurobiology Group, Department of Veterinary Clinical Studies, University of Glasgow, Glasgow G61 1QH, United Kingdom
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  • KLAUS-ARMIN NAVE

    Corresponding author
    1. Zentrum für Molekulare Biologie (ZMBH), University of Heidelberg, D-69120 Heidelberg, Germany
      eAddress for correspondence: Dr. Klaus-Armin Nave, Zentrum für Molekulare Biologie (ZMBH), Universität Heidelberg, Im Neuenheimer Feld 282, D-69120 Heidelberg, Germany; (49) 6221-546898 (voice); (49) 6221-545894 (fax); nave@sun0.urz.uni-heidelberg.de (e-mail).
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eAddress for correspondence: Dr. Klaus-Armin Nave, Zentrum für Molekulare Biologie (ZMBH), Universität Heidelberg, Im Neuenheimer Feld 282, D-69120 Heidelberg, Germany; (49) 6221-546898 (voice); (49) 6221-545894 (fax); nave@sun0.urz.uni-heidelberg.de (e-mail).

Abstract

ABSTRACT: We have generated a transgenic rat model of Charcot-Marie-Tooth disease type 1A (CMT1A) providing formal proof that this neuropathy can be caused by increased expression of peripheral myelin protein-22 (PMP22). Heterozygous PMP22-transgenic rats develop muscle weakness and gait abnormalities as well as reduced nerve conduction velocities and EMG abnormalities, which closely resemble recordings in patients with CMT1A. Dys- and demyelination, Schwann cell hypertrophy, and “onion bulb” formation are also similar to findings in humans. When bred to homozygosity, transgenic rats completely fail to elaborate myelin, but all myelin-forming Schwann cells segregate with axons in the normal one-to-one ratio. Although arrested at this “promyelin” stage, differentiation proceeds in homozygous rats at the molecular level, as demonstrated by high-level expression of myelin structural genes. Intracellular trafficking of the wild-type protein is not visibly impaired, even when strongly overexpressed, suggesting that PMP22 blocks myelin assembly in a late Golgi/cell membrane compartment of the affected Schwann cell.

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