Abnormal junctions and permeability of myelin in PMP22-deficient nerves

Ann Neurol. 2014 Feb;75(2):255-65. doi: 10.1002/ana.24086. Epub 2014 Feb 20.


Objective: The peripheral myelin protein-22 (PMP22) gene is associated with the most common types of inherited neuropathies, including hereditary neuropathy with liability to pressure palsies (HNPP) caused by PMP22 deficiency. However, the function of PMP22 has yet to be defined. Our previous study has shown that PMP22 deficiency causes an impaired propagation of nerve action potentials in the absence of demyelination. In the present study, we tested an alternative mechanism relating to myelin permeability.

Methods: Utilizing Pmp22(+) (/) (-) mice as a model of HNPP, we evaluated myelin junctions and their permeability using morphological, electrophysiological, and biochemical approaches.

Results: We show disruption of multiple types of cell junction complexes in peripheral nerve, resulting in increased permeability of myelin and impaired action potential propagation. We further demonstrate that PMP22 interacts with immunoglobulin domain-containing proteins known to regulate tight/adherens junctions and/or transmembrane adhesions, including junctional adhesion molecule-C (JAM-C) and myelin-associated glycoprotein (MAG). Deletion of Jam-c or Mag in mice recapitulates pathology in HNPP.

Interpretation: Our study reveals a novel mechanism by which PMP22 deficiency affects nerve conduction not through removal of myelin, but through disruption of myelin junctions.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Action Potentials / drug effects
  • Action Potentials / genetics
  • Age Factors
  • Animals
  • Arthrogryposis / genetics*
  • Arthrogryposis / metabolism*
  • Axons / drug effects
  • Axons / metabolism
  • Axons / pathology
  • Disease Models, Animal
  • Gene Expression Regulation / genetics
  • HEK293 Cells
  • Hereditary Sensory and Motor Neuropathy / genetics*
  • Hereditary Sensory and Motor Neuropathy / metabolism*
  • Humans
  • Junctional Adhesion Molecules / metabolism
  • Mice
  • Mice, Transgenic
  • Mutation / genetics
  • Myelin Proteins / deficiency*
  • Myelin Sheath / metabolism*
  • Neural Conduction / drug effects
  • Neural Conduction / genetics
  • Peripheral Nerves / metabolism
  • Peripheral Nerves / pathology
  • Potassium / pharmacology
  • Tight Junction Proteins / metabolism
  • Tight Junctions / genetics
  • Tight Junctions / metabolism
  • Tight Junctions / pathology*


  • Junctional Adhesion Molecules
  • Myelin Proteins
  • Pmp22 protein, mouse
  • Tight Junction Proteins
  • Potassium

Supplementary concepts

  • Tomaculous neuropathy