PMP22 overexpression causes dysmyelination in mice.

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 containing peripheral myelin protein 22 (PMP22) and its flanking controlling elements. We describe the behaviour of the C22 line (seven copies of YAC, 2.1 times PMP22 overexpression) during the myelination process. Electron microscopy, morphometry, electrophysiology, nerve conduction and expression of specific 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 fibroblasts, 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.