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Published online 17 May 2004. doi:10.1083/jcb.200402087
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 165, Number 4, 565-573
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Article

Pathology of a mouse mutation in peripheral myelin protein P0 is characteristic of a severe and early onset form of human Charcot-Marie-Tooth type 1B disorder



Annette E. Rünker1, Igor Kobsar2, Torsten Fink1, Gabriele Loers1, Thomas Tilling1, Peggy Putthoff1, Carsten Wessig2, Rudolf Martini2, and Melitta Schachner1

1 Center for Molecular Neurobiology, University of Hamburg, D-20246 Hamburg, Germany
2 Department of Neurology, Section of Developmental Neurobiology, Bayerische Julius-Maximilians University, D-97080 Würzburg, Germany

Address correspondence to Melitta Schachner, Zentrum für Molekulare Neurobiologie, Universität Hamburg, Martinistr. 52, D-20246 Hamburg, Germany. Tel.: (49) 40-42803-6246. Fax: (49) 40-42803-6248. email: melitta.schachner{at}zmnh.uni-hamburg.de

Mutations in the gene of the peripheral myelin protein zero (P0) give rise to the peripheral neuropathies Charcot-Marie-Tooth type 1B disease (CMT1B), Déjérine-Sottas syndrome, and congenital hypomyelinating neuropathy. To investigate the pathomechanisms of a specific point mutation in the P0 gene, we generated two independent transgenic mouse lines expressing the pathogenic CMT1B missense mutation Ile106Leu (P0sub) under the control of the P0 promoter on a wild-type background. Both P0sub-transgenic mouse lines showed shivering and ultrastructural abnormalities including retarded myelination, onion bulb formation, and dysmyelination seen as aberrantly folded myelin sheaths and tomacula in all nerve fibers. Functionally, the mutation leads to dispersed compound muscle action potentials and severely reduced conduction velocities. Our observations support the view that the Ile106Leu mutation acts by a dominant-negative gain of function and that the P0sub-transgenic mouse represents an animal model for a severe, tomaculous form of CMT1B.

Key Words: myelin P0 protein; myelin; peripheral neuropathies; tomacula; dominant-negative effects

A.E. Rünker and I. Kobsar contributed equally to this paper.

R. Martini and M. Schachner contributed equally to this paper.

A.E. Rünker's present address is Developmental Neurobiology, Department of Genetics, Smurfit Institute, Trinity College Dublin, Dublin 2, Ireland.

Abbreviations used in this paper: CMT, Charcot-Marie-Tooth disease; DSS, Déjérine-Sottas syndrome; P0, peripheral myelin protein zero.


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