Peripheral myelin protein 2 - a novel cluster of mutations causing Charcot-Marie-Tooth neuropathy

Orphanet J Rare Dis. 2019 Aug 14;14(1):197. doi: 10.1186/s13023-019-1162-x.


Background: Charcot-Marie-Tooth (CMT) disease is the most common inherited neuromuscular disorder characterized by wide clinical, genetic and pathomechanistic heterogeneity. Recently, the gene encoding peripheral myelin protein 2 (PMP2) was identified as a novel cause for CMT neuropathy with three mutations that structurally cluster together (p.Ile43Asn, p.Thr51Pro, p.Ile52Thr) reported in five families.

Results: Using whole exome sequencing and cohort screening we identified two novel missense substitutions in PMP2 in Bulgarian (p.Met114Thr, c.341C > T) and German (p.Val115Ala, c.344 T > C) families. The mutations affect adjacent and highly conserved amino acid residues outside of the known mutation-rich region in the protein. Crystal structure analysis positions the affected residues within a cluster of highly conserved fatty acid coordinating residues implying their functional significance. The clinical, electrophysiological and imaging features in both families were consistent with a childhood onset polyneuropathy with variable patterns of demyelination, slow to very slow progression, and most severe involvement of the peroneal muscles.

Conclusions: We expand the genetic and phenotypic spectrum of PMP2-related peripheral neuropathy. Our findings reveal a second mutational cluster in the protein.

Keywords: CMT; Cluster; Demyelinating; Novel; PMP2.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Charcot-Marie-Tooth Disease / etiology*
  • Charcot-Marie-Tooth Disease / genetics*
  • Child
  • Child, Preschool
  • Female
  • Humans
  • Infant
  • Male
  • Middle Aged
  • Mutation
  • Myelin P2 Protein / genetics*
  • Pedigree
  • Phenotype
  • Whole Exome Sequencing
  • Young Adult


  • Myelin P2 Protein
  • PMP2 protein, human