MpzR98C arrests Schwann cell development in a mouse model of early-onset Charcot-Marie-Tooth disease type 1B

Mario A.C. Saporta, Brian R. Shy, Agnes Patzko, Yunhong Bai, Maria Pennuto, Cinzia Ferri, Elisa Tinelli, Paola Saveri, Dan Kirschner, Michelle Crowther, Cherie Southwood, Xingyao Wu, Alexander Gow, M. Laura Feltri, Lawrence Wrabetz, Michael E. Shy

Research output: Contribution to journalArticle

34 Scopus citations

Abstract

Mutations in myelin protein zero (MPZ) cause Charcot-Marie-Tooth disease type 1B. Many dominant MPZ mutations, including R98C, present as infantile onset dysmyelinating neuropathies. We have generated an R98C 'knock-in' mouse model of Charcot-Marie-Tooth type 1B, where a mutation encoding R98C was targeted to the mouse Mpz gene. Both heterozygous (R98C/ +) and homozygous (R98C/R98C) mice develop weakness, abnormal nerve conduction velocities and morphologically abnormal myelin; R98C/R98C mice are more severely affected. MpzR98C is retained in the endoplasmic reticulum of Schwann cells and provokes a transitory, canonical unfolded protein response. Ablation of Chop, a mediator of the protein kinase RNA-like endoplasmic reticulum kinase unfolded protein response pathway restores compound muscle action potential amplitudes of R98C/ + mice but does not alter the reduced conduction velocities, reduced axonal diameters or clinical behaviour of these animals. R98C/R98C Schwann cells are developmentally arrested in the promyelinating stage, whereas development is delayed in R98C/ + mice. The proportion of cells expressing c-Jun, an inhibitor of myelination, is elevated in mutant nerves, whereas the proportion of cells expressing the promyelinating transcription factor Krox-20 is decreased, particularly in R98C/R98C mice. Our results provide a potential link between the accumulation of MpzR98C in the endoplasmic reticulum and a developmental delay in myelination. These mice provide a model by which we can begin to understand the early onset dysmyelination seen in patients with R98C and similar mutations.

Original languageEnglish (US)
Pages (from-to)2032-2047
Number of pages16
JournalBrain
Volume135
Issue number7
DOIs
StatePublished - Jul 2012

Keywords

  • Charcot-Marie-Tooth type 1B
  • Demyelination
  • Glial cells
  • Neuromuscular disorders
  • Neuropathy

ASJC Scopus subject areas

  • Clinical Neurology

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    Saporta, M. A. C., Shy, B. R., Patzko, A., Bai, Y., Pennuto, M., Ferri, C., Tinelli, E., Saveri, P., Kirschner, D., Crowther, M., Southwood, C., Wu, X., Gow, A., Feltri, M. L., Wrabetz, L., & Shy, M. E. (2012). MpzR98C arrests Schwann cell development in a mouse model of early-onset Charcot-Marie-Tooth disease type 1B. Brain, 135(7), 2032-2047. https://doi.org/10.1093/brain/aws140