A Mutation in PMP2 Causes Dominant Demyelinating Charcot-Marie-Tooth Neuropathy

PLoS Genet. 2016 Feb 1;12(2):e1005829. doi: 10.1371/journal.pgen.1005829. eCollection 2016 Feb.


Charcot-Marie-Tooth disease (CMT) is a heterogeneous group of peripheral neuropathies with diverse genetic causes. In this study, we identified p.I43N mutation in PMP2 from a family exhibiting autosomal dominant demyelinating CMT neuropathy by whole exome sequencing and characterized the clinical features. The age at onset was the first to second decades and muscle atrophy started in the distal portion of the leg. Predominant fatty replacement in the anterior and lateral compartment was similar to that in CMT1A caused by PMP22 duplication. Sural nerve biopsy showed onion bulbs and degenerating fibers with various myelin abnormalities. The relevance of PMP2 mutation as a genetic cause of dominant CMT1 was assessed using transgenic mouse models. Transgenic mice expressing wild type or mutant (p.I43N) PMP2 exhibited abnormal motor function. Electrophysiological data revealed that both mice had reduced motor nerve conduction velocities (MNCV). Electron microscopy revealed that demyelinating fibers and internodal lengths were shortened in both transgenic mice. These data imply that overexpression of wild type as well as mutant PMP2 also causes the CMT1 phenotype, which has been documented in the PMP22. This report might expand the genetic and clinical features of CMT and a further mechanism study will enhance our understanding of PMP2-associated peripheral neuropathy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Charcot-Marie-Tooth Disease / genetics*
  • Charcot-Marie-Tooth Disease / pathology
  • Charcot-Marie-Tooth Disease / physiopathology
  • Chromosome Segregation
  • Computer Simulation
  • Demyelinating Diseases / genetics*
  • Electrophysiological Phenomena
  • Family
  • Female
  • Genes, Dominant*
  • HEK293 Cells
  • Humans
  • Leg / physiopathology
  • Magnetic Resonance Imaging
  • Male
  • Mice, Transgenic
  • Molecular Sequence Data
  • Mutation
  • Myelin P2 Protein / chemistry
  • Myelin P2 Protein / genetics*
  • Pedigree
  • Phenotype
  • Sural Nerve / pathology
  • Sural Nerve / physiopathology


  • Myelin P2 Protein
  • PMP2 protein, human

Grants and funding

This study was supported by the Korean Health Technology R&D Project, Ministry of Health & Welfare (HI12C0135 and HI14C3484) and by the National Research Foundation of Korea (NRF) grants funded by the Korea governments, MSIP (NRF-2014R1A2A2A01004240). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.