PMP22 carrying the trembler or trembler-J mutation is intracellularly retained in myelinating Schwann cells.
Missense mutations in the murine peripheral myelin protein-22 gene (Pmp22) underly the neuropathies in the trembler (Tr) and trembler-J (Tr-J) mice and in some humans with Charcot-Marie-Tooth disease. We have generated replication-defective adenoviruses containing epitope-tagged, wild-type-, Tr-, or Tr-J-PMP22 bicistronic with the Lac-Z reporter gene. These viruses were microinjected into the sciatic nerves of 10-day-old Sprague-Dawley rats and, later, analyzed by immunohistochemistry to determine the distribution of mutant protein in infected myelinating Schwann cells. We found that epitope-tagged, wild-type PMP22 is successfully transported to compact myelin, whereas the Tr and the Tr-J mutant proteins are retained in cytoplasmic compartment, colocalizing with the endoplasmic reticulum. These results provide in vivo evidence that the pathogenesis of the Tr and Tr-J mutations are most likely a function of abnormal retention within the endoplasmic reticulum of myelinating Schwann cells.
Colby
J
J
Department of Pathology, McGill University, Zürich, Switzerland.
Nicholson
R
R
Dickson
K M
KM
Orfali
W
W
Naef
R
R
Suter
U
U
Snipes
G J
GJ
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D002460:Cell Line; D002607:Charcot-Marie-Tooth Disease / Q000209:etiology / Q000235:genetics; D004721:Endoplasmic Reticulum / Q000378:metabolism; D000939:Epitopes / Q000235:genetics; D017930:Genes, Reporter; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry; D007424:Intracellular Fluid / Q000378:metabolism*; D051379:Mice; D008818:Mice, Neurologic Mutants / Q000235:genetics; D008845:Microinjections; D020125:Mutation, Missense / Q000235:genetics; D009185:Myelin Proteins / Q000235:genetics* / Q000378:metabolism*; D009186:Myelin Sheath / Q000378:metabolism*; D021381:Protein Transport / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D012583:Schwann Cells / Q000166:cytology / Q000378:metabolism*; D012584:Sciatic Nerve / Q000187:drug effects / Q000378:metabolism / Q000473:pathology
D000939:Epitopes; D009185:Myelin Proteins; C073687:PMP22 protein, human; C489545:Pmp22 protein, mouse; C489546:Pmp22 protein, rat