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 an d in some humans with Charcot-Marie-Tooth disease. We have generated replic ation-defective adenoviruses containing epitope-tagged, wild-type-, Tr-, or Tr-J-PMP22 bicistronic with the Lac-Z reporter gene. These viruses were mi croinjected into the sciatic nerves of 10-day-old Sprague-Dawley rats and, later, analyzed by immunohistochemistry to determine the distribution of mu tant protein in infected myelinating Schwann cells. We found that epitope-t agged, wild-type PMP22 is successfully transported to compact myelin, where as the Tr and the Tr-J mutant proteins are retained in cytoplasmic compartm ent, colocalizing with the endoplasmic reticulum. These results provide in vivo evidence that the pathogenesis of the Tr and Tr-J mutations are most l ikely a function of abnormal retention within the endoplasmic reticulum of myelinating Schwann cells, (C) 2000 Academic Press.