PMP22 overexpression causes dysmyelination in mice

A. Robaglia-Schlupp
2002 Brain  
Charcot±Marie±Tooth (CMT) disease is the most frequent hereditary peripheral neuropathy in humans. Its prevalence is about one in 2500. A subform, CMT1A, is transmitted as an autosomal dominant trait. An estimated 75% of patients are affected. This disorder has been shown to be associated with the duplication of a 1.5 Mb region of the short arm of chromosome 17, in which the PMP22 gene has been mapped. We have constructed a murine model of CMT1A by inserting into the murine genome a human YAC
more » ... enome a human YAC containing peripheral myelin protein 22 (PMP22) and its¯anking controlling elements. We describe the behaviour of the C22 line (seven copies of YAC, 2.1 times PMP22 overexpression) during the myelination process. Electron micro-scopy, morphometry, electrophysiology, nerve conduction and expression of speci®c markers (e.g. Krox20) in normal and pathological Schwann cells demonstrated that PMP22 overexpression leads to a defect in the myelination of axons. The largest axons are the most affected. Only a few demyelination/remyelination processes were observed. Moreover, PMP22 overexpression probably enhances collagen synthesis by ®broblasts, before myelination, demonstrating that structures other than Schwann cells are affected by PMP22 overexpression. Classically, CMT1A was thought to be induced by a demyelination process following a phase of normal myelination, yet our data suggest that dysmyelination should be considered as a major factor for the disease. Abbreviations: CMT = Charcot±Marie±Tooth disease; MBP = myelin basic protein; P = post-natal stage; PMP22 = peripheral myelin protein 22
doi:10.1093/brain/awf230 pmid:12244079 fatcat:7lnif2cf5nho7aee5lscq3txta