Hypermyelination and demyelinating peripheral neuropathy in Pmp22-deficient mice

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Peripheral myelin protein PMP22 has been suggested to have a role in peripheral nerve myelination and cell proliferation. Defects at the PMP22 locus are associated with peripheral neuropathies such as Charcot–Marie–Tooth disease type 1 A. We now demonstrate that mice devoid of Pmp22 are retarded in the onset of myelination and develop abundant sausage–like hypermyelination structures (tomacula) at a young age followed by severe demyelination, axonal loss and functional impairment. Mice carrying one functional copy of Pmp22 are less affected but they also exhibit focal tomacula comparable to the morphological features in hereditary neuropathy with liability to pressure palsies (HNPP). We conclude that Pmp22 is required for the correct development of peripheral nerves, the maintenance of axons and the determination of myelin thickness and stability.

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  1. 1

    Peters, A., Palay, S.L. & Webster, H. deF. in The fine structure of the nervous system. 212–272. (Oxford University Press, Oxford, 1991).

  2. 2

    Snipes, G.J. & Suter, U. Molecular anatomy and genetics of myelin proteins in the peripheral nervous system. J. Anat. 186, 483–494 (1995).

  3. 3

    Welcher, A.A., Suter, U., De Leon, M., Snipes, G.J. & Shooter, E.M. A myelin protein is encoded by the homotogue of a growth arrest-specific gene. Proc. natl. Acad. Sci. U.S.A. 88, 7196–7199 (1991).

  4. 4

    Spreyer, P. et al. Axon-regulated expression of a Schwann cell transcript that is homologous to a ‘growth arrest-specific’ gene. EMBO J. 10, 3661–3668 (1991).

  5. 5

    Snipes, G.J., Suter, U., Weteher, A.A. & Shooter, E.M. Characterization of a novel peripheral nervous system myelin protein (PMP-22/SR13). J. Cell Biol. 117, 225–238 (1992).

  6. 6

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

  7. 7

    Suter, U., Welcher, A.A. & Snipes, G.J. Progress in the molecular understanding of hereditary peripheral newopatNes reveals new insights into the biology of the peripheral nervous system. Trends Neurosci. 16, 50–66 (1993).

  8. 8

    Parmantier, E., Gabon, R., Braun, C., D'Urso, D., Müller, H.W. & Zalc, B. Peripheral myelin protein-22 is expressed in rat and mouse brain and spinal cordmotoneurons. Eur. J. Neurosci. 7, 1080–1088 (1995).

  9. 9

    Baecher, D. et al. Widespread expression of the peripheral myelin protein-22 gene (pmp22) in neural and non-neural tissues during murine development. J. neurosci. Res. (in the press).

  10. 10

    Manfioletti, G., Ruaro, M.E., Del Sal, G., Philipson, L. & Schneider, C. A growth arrest-specific (gas) gene codes for a membrane protein. Molec. cell. Biol. 10, 2924–2930 (1990).

  11. 11

    Zoidl, G., Blass-Kampmann, S., D'Urso, D., Schmatenbach, C. & Müller, H.W. Retroviral-mediated gene transfer of the peripheral myelin protein PMP22 in Schwann cells: modulation of cell growth. EMBO J. 14, 1122–1128 (1995).

  12. 12

    Suter, U. & Snipes, G.J. Peripheral myelin protein PMP22: Facts and hypotheses. J. neurosci. Res. 40, 145–151 (1995).

  13. 13

    Suter, U. et al. Regulation of alternative peripheral myelin protein-22 (PMP22) gene transcripts by two promoters. J. biol. Chem. 269, 25795–25806 (1994).

  14. 14

    Suter, U. & Snipes, G.J. Biology and genetics of hereditary motor and sensory neuropathies. A. Rev. Neurosci. 18, 45–75 (1995).

  15. 15

    Skre, H. Genetic and clinical aspects of Crarcot-Marie-Tooth's disease. Clin. Genet. 6, 98–118 (1974).

  16. 16

    Lupski, J.R. et al. DMA duplication associated with Charcot-Marie-Tooth disease type 1A. Cell 66, 219–232 (1991).

  17. 17

    Raeymaekers, P. et al. Duplication in chromosome 17p11.2 in Charcot-Marie-Tooth neuropathy type 1a (CMT 1a). The HMSN Collaborative Research Group. Neuromusc. Dis. 1, 93–97 (1991).

  18. 18

    Chance, P.F. et al. DNA deletion associated with hereditary neuropathy with liability to pressure palsies. Cell 72, 143–151 (1993).

  19. 19

    Pentao, L., Wise, C.A., Chinautt, A.C., Patel, P.I. & Lupski, J.R. Charcot-Marie-Tooth type 1A duplication appears to arise from recombination at repeat sequences flanking the 1.5 Mb monomer units. Nature Genet. 2, 292–300 (1992).

  20. 20

    Chance, P.P. et al. Two autosomai dominant neuropathies result from reciprocal DNA dupKcatiorVcleletion of a region on chromosome 17. Hum. molec. Genet. 3, 323–328 (1994).

  21. 21

    Suter, U. et al. Trembler mouse carries a point mutation in a myefin gene. Nature 368, 241–244 (1992).

  22. 22

    Suter, U. et al. A teucine to proNne mutation in the putative first transmembrane domain of the 22 kDa peripheral myelin protein in the Trembier-J mouse. Proc. natnl. Acad. Sci. USA. 89, 4382–4386 (1992).

  23. 23

    Patel, P. et al. The gene for the peripheral myelin protein PMP-22 is a candidate for Charcot-Marie-Tooth disease type 1A. Nature Genet. 1, 159–165 (1992).

  24. 24

    Valentijn, L.J. et al. The peripheral myelin gene PMP-22/GAS-3 is duplicated in Charcot-Marie-Tooth disease type lA. Nature Genet. 1, 166–170 (1992).

  25. 25

    Timmerman, V. et al. The peripheral myelin protein gene PMP-22 is contained within the Charcot-Marie-Tooth disease type 1A duplication. Nature Genet. 1, 171–175 (1992).

  26. 26

    Matsunami, N. et al. Peripheral myelin protein-22 gene maps in the duplication in chromosome 17p11.2 associated with Charcot-Marie-Tooth 1A. Nature Genet. 1, 176–179 (1992).

  27. 27

    Vatentijn, L.J. et al. Identical point mutations of PMP-22 in Trembter-J mouse and Charcot-Marie-Tooth disease type 1a. Nature Genet. 2, 288–291 (1992).

  28. 28

    Roa, B.B. et al. Charcot-Marie-Tooth disease type 1A: Association with a spontaneous point mutation in the PMP22 gene. New Engl. J. Med. 329, 96–101 (1993).

  29. 29

    Roa, B.B. et al. Evidence for a recessive PMP22 point mutation in Charcot-Marte-Tooth disease type 1A. Nature Genet. 5, 189–194 (1993).

  30. 30

    Roa, B.B., Dyck, P.J., Marks, H.G., Chance, P.F. & Lupski, J.R. Dejerine-Sottas syndrome associated with point mutation in the peripheral myelin protein 22 (PMP22) gene. Nature Genet. 5, 269–272 (1993).

  31. 31

    Vatentijn, U., Ouvrier, R.A., van den Bosch, N.H., Bolhuis, P.A., Baas, F. & Nicholson, G.A. Dejerine-Sottas neuropathy is associated with a de novo PMP22 mutation. Hum. Mut. 5, 76–80 (1995).

  32. 32

    Nicholson, G.A. et al. A frame shift mutation in the PMP22 gene in hereditary neuropathy with liability to pressure palsies. Nature Genet. 6, 263–266 (1994).

  33. 33

    Dyck, P.J., Chance, P.F., Lebo, R.V. & Carney, J.A. Hereditary motor and sensory neuropathies. in Peripheral Neuropathy, 3rd edition (eds Dyck, P.J. et al.) 1094–1136 (Saunders, PhHaddphia, 1993).

  34. 34

    Windebank, A.J. Inherited recurrent focal neuropathies. In Peripheral Neuropathy, 3rd edition (eds Dyck, P.J. et al.) 1137–1148 (Saunders, Philadelphia, 1993).

  35. 35

    Meier, C. & Moll, C.K. Hereditary neuropathy with liability to pressure palsies. J. Neurol. 228, 73–95 (1962).

  36. 36

    Pareek, S. et al. Detection and processing of peripheral myelin protein PMP22 in cultured Schwann cells. J. biol. Chem. 268, 10372–10379 (1993).

  37. 37

    Falconer, D.S. Two new mutants, ‘trembler’ and ‘reefer’ with neurological actions in the house mouse (Mus musculus L.). Genetics 50, 192–501 (1951).

  38. 38

    Uncini, A. et al. Differential etectrophysidogical features of neuropathies associated with 17p11.2 deletion and duplication. Muscle & Nerve 18, 628–635 (1995).

  39. 39

    Montag, D. et al. Mice deficient for the myelin-associated glycoprotein show subtle abnormalities in myelin. Neuron 13, 229–546 (1994).

  40. 40

    Martini, R., Mohajeri, M.H., Kasper, S., Giese, K.P. & Schachner, M. Mice doubly deficient in the genes for P0 and myelin baste protein show that both proteins contribute to the formation of the major dense line in peripheral nerve myelin. J. Neurosci. 15, 4488–4495 (1995).

  41. 41

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

  42. 42

    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, 565–576 (1992).

  43. 43

    Martini, R., Zielasek, J., Toyka, K.V., Giese, K.P. & Schachner, M. Protein zero (P0)-deficient mice show myelin degeneration in peripheral nerves characteristic of inherited human neuropathies. Nature Genet. 11, 281–286 (1995).

  44. 44

    Aguayo, A.J., Attiwell, M., Trecarten, J., Perkins, S. & Bray, G.M. Abnormal myelination in transplanted trembler mouse Schwann cells. Nature 265, 73–75 (1977).

  45. 45

    de Waegh, S.M., Lee, V.M.-Y. & Brady, S.T. Local modulation of neurofilament phosphorylation axonal caliber and stow axonal transport by myelinating Schwann cells. Cell 68, 451–463 (1992).

  46. 46

    Collelo, R.J., Pott, U. & Schwab, M.E. The role of oligodendrocytes and myelin on axon maturation in the developing rat retinofugal pathway. J. Neurosci. 14, 2594–5605 (1994).

  47. 47

    Ellis, D. & Malcolm, S. Proteolipid protein gene dosage effect in Pelizaeus-Merzbacher disease. Nature Genet. 6, 333–334 (1994).

  48. 48

    Thomas, F.R. et al. Tomacutous neuropathy in chromosome 1 Charcot-Marie-Tooth syndrome. Acta Neuropathol. 87, 91–97 (1994).

  49. 49

    Dyck, P.J., Kames, J., Lais, H., Lofgren, E.P. & Stevens, J.C. Pathologic alterations of the peripheral nervous system of humans. In Peripheral Neuropathy, 2nd edition (eds Dyck, P.J. et al.) 760–870 (Saunders, Philadelphia, 1984).

  50. 50

    Henry, E.W., Cowen, J.S. & SkJman, R.L. Comparison of Trembler and Trembter-J mouse phenotypes: Varying severity of peripheral hyporrryelination. J. Neuropathol. exp. Neurol. 42, 688–706 (1983).

  51. 51

    Low, P.A. & McLeod, J.G. Refractory period conduction of trains impulses and effect of temperature on conduction in chronic hypertrophte neuropathy. Etectrophysiotogical studies on the Trembler mouse. J. Neurol. Neurosurg. Psych. 40, 434–447 (1977).

  52. 52

    Taytor, V., Welcher, A.R., Amgen Est, Program & Suter, U. Epithelial rrambrane protein-1, peripheral myelin protein 22 and lens nwmbraie protein 20 define a novel gene family. J. biol. Chem. (in the press).

  53. 53

    Ruffner, H., Reis, L.F.L., Näf, D. & Weissmann, C. Induction of type I interferon genes and interferon-inducible genes in embryonal stem cells devoid of interferon-regdatory factor 1. Proc. natl. Acad. Sci. USA 90, 11503–11507 (1993).

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Adlkofer, K., Martini, R., Aguzzi, A. et al. Hypermyelination and demyelinating peripheral neuropathy in Pmp22-deficient mice. Nat Genet 11, 274–280 (1995) doi:10.1038/ng1195-274

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