title: Abnormal junctions and permeability of myelin in PMP22-deficient nerves.
abstract: 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.
  
  
  CONCLUSIONS
  Our study reveals a novel mechanism by which PMP22 deficiency affects nerve conduction not through removal of myelin, but through disruption of myelin junctions.
authors: Department of Neurology, Center for Human Genetics Research, Vanderbilt Brain Institute, Vanderbilt University School of Medicine, Nashville, TN.
authors: Jiasong
authors: J
authors: Guo
authors: Leiming
authors: L
authors: Wang
authors: Yang
authors: Y
authors: Zhang
authors: Jiawen
authors: J
authors: Wu
authors: Sezgi
authors: S
authors: Arpag
authors: Bo
authors: B
authors: Hu
authors: Beat A
authors: BA
authors: Imhof
authors: Xinxia
authors: X
authors: Tian
authors: Bruce D
authors: BD
authors: Carter
authors: Ueli
authors: U
authors: Suter
authors: Jun
authors: J
authors: Li
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000235:genetics; D000367:Age Factors; D000818:Animals; D001176:Arthrogryposis / Q000235:genetics* / Q000378:metabolism*; D001369:Axons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000235:genetics; D057809:HEK293 Cells; D015417:Hereditary Sensory and Motor Neuropathy / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D062726:Junctional Adhesion Molecules / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D009185:Myelin Proteins / Q000172:deficiency*; D009186:Myelin Sheath / Q000378:metabolism*; D009431:Neural Conduction / Q000187:drug effects / Q000235:genetics; D010525:Peripheral Nerves / Q000378:metabolism / Q000473:pathology; D011188:Potassium / Q000494:pharmacology; D062725:Tight Junction Proteins / Q000378:metabolism; D019108:Tight Junctions / Q000235:genetics / Q000378:metabolism / Q000473:pathology*
chemical_list: D062726:Junctional Adhesion Molecules; D009185:Myelin Proteins; C489545:Pmp22 protein, mouse; D062725:Tight Junction Proteins; D011188:Potassium