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Protein zero (P0)–deficient mice show myelin degeneration in peripheral nerves characteristic of inherited human neuropathies

Nature Genetics volume 11, pages 281–286 (1995)Cite this article

Abstract

Mutations in the human gene for the myelin recognition molecule protein zero (P0) give rise to severe and progressive forms of dominantly inherited peripheral neuropathies. We have previously reported that mice homozygous for a null mutation in P0 have severely hypomyelinated nerves ten weeks after birth. Here we show hypomyelination already exists at day four with subsequent demyelination and impaired nerve conduction. Furthermore, heterozygous mutants show normal myelination, but develop progressive demyelination after four months of age. Thus, the pathology of homo– and heterozygous P0 mutants resembles that of the severely affected Déjérine–Sottas and the more mildly affected Charcot–Marie–Tooth type 1B patients, respectively.

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References

  1. Giese, K.P., Martini, R., Lemke, G., Soriano, P. & Schachner, M. Mouse P0 gene disruption leads to hypomyelination, abnormal expression of recognition molecules, and degeneration of myelin and axons. Cell 71, 565–676 (1992).

    Article  CAS  Google Scholar 

  2. Hayasaka, K. et al. Charcot-Marie-Tooth neuropathy type 1B is associated with mutations of the myelin P0 gene. Nature Genet 5, 31–34 (1993).

    Article  CAS  Google Scholar 

  3. Hayasaka, K. et al. De novo mutation of the myelin P0 gene in Dejerine-Sottas disease (hereditary motor and sensory neuropathy type III). Nature Genet. 5, 266–268 (1993).

    Article  CAS  Google Scholar 

  4. Hayasaka, K., Ohnishi, A., Takada, G., Fukushima, Y. & Murai, Y. Mutation of the myelin P0 gene in Charcot-Marie-Tooth neuropathy type 1. Biochem. biophys. Res. Comm. 194, 1317–1322 (1993).

    Article  CAS  Google Scholar 

  5. Hayasaka, K., Takada, G. & lonasescu, V.V. Mutation of the myelin P0 gene in Charcot-Marie-Tooth neuropathy type 1B. Hum. molec. Genet. 2, 1369–1372 (1993).

    Article  CAS  Google Scholar 

  6. Himoro, M. et al. New mutation of the myelin P0 gene in a pedigree of Charcot-Marie-Tooth neuropathy type 1 Biochem. molec. Biol. Int. 31, 169–173 (1993).

    CAS  PubMed  Google Scholar 

  7. Kulkens, T. et al. Deletion of the serine 34 codon from the major peripheral myelin protein P0 gene in Charcot-Marie-Tooth disease type 1B. Nature Genet. 5, 35–39 (1993).

    Article  CAS  Google Scholar 

  8. Su, Y. et al. Myelin protein zero gene mutated in Charcot-Marie-Tooth type 1B patients. Proc. natl. Acad. Sci. U.S.A. 90, 10856–10860 (1993).

    Article  CAS  Google Scholar 

  9. Nelis, E. et al. Linkage and mutation analysis in an extended family with Charcot-Marie-Tooth disease 1B. J. mod. Genet. 31, 811–815 (1994).

    Article  CAS  Google Scholar 

  10. Rautenstrauß, B., Nelis, E., Grehl, H., Pfeiffer, R.A. & Van Broeckhoven, C. Identification of a de novo insertions mutation in P0 in a patient with a Déjérine-Sottas syndrome (DSS) phenotype. Hum. molec. Genet. 3, 1701–1702 (1994).

    Article  Google Scholar 

  11. Martini, R., Mohajeri, M.H., Kasper, S., Giese, K.P. & Schachner, M. Mice doubly deficient in the genes for P0 and myelin basic protein show that both proteins contribute to the formation of the major dense line in peripheral nerve myelin. J. Neurosci. 15, 4488–4495.

    Article  CAS  Google Scholar 

  12. Dyck, P.J., Chance, P., Lebo, R. & Carney, J.I. Hereditary motor and sensory neuropathies. in Peripheral Neuropathy 3rd edn. (eds Dyck, R.J. et al.) 1094–1136 (Saunders, Philadelphia, 1993).

    Google Scholar 

  13. Landon, D.N. & Hall, S. The myelinated nerve fibre, in The Peripheral Nerve (ed. Landon, D.N.) 1–90 (Chapman & Hall, London, 1976).

    Google Scholar 

  14. Reynolds, R.J., Little, G.J., Lin, M. & Heath, J.W. Imaging myelinated nerve fibres by confocal fluorescence microscopy: individual fibres in whole nerve trunks traced through multiple consecutive internodes. J. Neurocytol. 23, 555–564 (1994).

    Article  CAS  Google Scholar 

  15. Martini, R., Schachner, M. & Faissner, A. Enhanced expression of the extraceltuiar matrix moiecule J1/tenascin in the regenerating adult mouse sciatic nerve. J. Neurocytol. 19, 601–616 (1990).

    Article  CAS  Google Scholar 

  16. Fruttiger, M., Schachner, M. & Martini, R. Tenascin-C expression during Wallerian degeneration in C57BL/Wlds mice: P0ssible implications for axonal regeneration. J. Neurocytol. 24, 1–14 (1995).

    Article  CAS  Google Scholar 

  17. Fruttiger, M., Montag, D., Schachner, M. & Martini, R. Crucial role for the myelin-associated glycoprotein for the maintenance of axon-myelin integrity. Eur. J. Neurosci. 7, 511–615 (1995).

    Article  CAS  Google Scholar 

  18. Tachi, N., Ishikawa, Y. & Minami, R. Two cases of congenital hyP0myelination neuropathy. Brain Devi. 6, 560–565 (1984).

    Article  CAS  Google Scholar 

  19. Ouvrier, R.A., McLeod, J.G. & Conchin, T.E. The hypertrophic forms of hereditary motor and sensory neuropathy. Brain 110, 121–148 (1987).

    Article  Google Scholar 

  20. Hoogendijk, J.E. et al. Ultrastrucutral features of defective myelination in hereditary motor and sensory neuropathy type 1B (abstract). J. Neurol. 242 [Suppl. 2], 149 (1995).

    Google Scholar 

  21. Uchida, Y., Tomonaga, M. & Nomura, K. Age-related changes of myelin proteins in the rat peripheral nervous system. J. Neurochem. 46, 1376–1381 (1986).

    Article  CAS  Google Scholar 

  22. Mitchell, L.S. et al. Expression of myelin protein gene transcripts by Schwann cells of regenerating nerve. J. neurosci. Res. 27, 125–135 (1990).

    Article  CAS  Google Scholar 

  23. Shine, H.D., Readhead, C., Popko, B., Hood, L. & Sidman, R.L. Morphometric analysis of normal mutant and transgenic CNS: correlation of myelin basic protein expression to myelinogenesis. J. Neurochem. 58, 342–349 (1992).

    Article  CAS  Google Scholar 

  24. Nave, K.-A. Neurological mouse mutants and the genes of myelin. J. neurosci. Res. 38, 607–612 (1994).

    Article  CAS  Google Scholar 

  25. Suter, U., Welcher, A.A. & Snipes, G.J. Progress in the molecular understanding of hereditary peripheral neuropathies reveals new insights into the biology of the peripheral nervous system. Trends Neurosci. 16, 50–56 (1993).

    Article  CAS  Google Scholar 

  26. Adlkofer, K. et al. Hypermyelination and demyelinating peripheral neuropathy in Pmp22-deficient mice. Nature Genet. 11, 274–280 (1995).

    Article  CAS  Google Scholar 

  27. Gow, A., Friedrich, V.L. & Lazzarini, R.A. Many naturally occurring mutations of myelin proteolipid protein impair its intracellular transP0rt. J. neurosci. Res. 37, 574–583 (1994).

    Article  CAS  Google Scholar 

  28. Kirschner, D.A. & Saavedra, R.A. Mutations in demyelinating peripheral neuropathies supP0rt molecular model of myelin P0–glycoprotein extracellular domain. J. neurosci. Res. 39, 63–69 (1994).

    Article  CAS  Google Scholar 

  29. Husmann, K., Faissner, A. & Schachner, M. Tenascin promotes cerebellar granule cell migration and neurite outgrowth by different domains in the fibronectin type III repeats. J. Cell Biol. 116, 1475–1486 (1992).

    Article  CAS  Google Scholar 

  30. Montag, D. et al. Mice deficient for the myelin-associated glycoprotein show subtle abnormalities in myelin. Neuron 13, 229–246 (1994).

    Article  CAS  Google Scholar 

  31. Hartung, H.R., SchSfer, B., Heininger, K., Stoll, G. & Toyka, K.V. The role of macrophages and eicosanoids in the pathogenesis of experimental allergic neuritis. Serial clinical, electrophysiological, biochemical, and morphological observations. Brain 111, 1039–1059 (1988).

    Article  Google Scholar 

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Author notes

  1. K. Peter Giese

    Present address: Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, 11724, USA

Authors and Affiliations

  1. Department of Neurobiology, Swiss Federal Institute of Technology, Hönggerberg, CH-8093, Zürich, Switzerland

    Rudolf Martini, K. Peter Giese & Melitta Schachner

  2. Neurologische Universitätsklinik, Josef-Schneider-Strasse 11, Würzburg, D-97080, Germany

    Jürgen Zielasek & Klaus V. Toyka

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  4. K. Peter Giese
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  5. Melitta Schachner
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Martini, R., Zielasek, J., Toyka, K. et al. Protein zero (P0)–deficient mice show myelin degeneration in peripheral nerves characteristic of inherited human neuropathies. Nat Genet 11, 281–286 (1995). https://doi.org/10.1038/ng1195-281

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