Type 1A dsysmelination research from France

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(Recent CMT 1A research abstract)

1: Brain 2002 Oct;125(Pt 10):2213-21

PMP22 overexpression causes dysmyelination in mice.

Robaglia-Schlupp A, Pizant J, Norreel JC, Passage E, Saberan-Djoneidi D,

Ansaldi JL, Vinay L, Figarella-Branger D, Levy N, Clarac F, Cau P,

Pellissier JF, Fontes M.

INSERM U491, Medical Genetics and Development, Faculte de Medecine de la

Timone, 27 Boulevard J. Moulin, 13385 Marseille cedex 5, France.

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 erexpression probably enhances collagen

synthesis by fibroblasts, before dsysmelination, 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.