Animal Models of CMT 1A

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Neuromolecular Med. 2006;8(1-2):205-16.

Animal Models of Charcot-Marie-Tooth Disease Type 1A.

Sereda MW, Nave KA.

Department of Neurogenetics, Max-Planck-Institute of Experimental

Medicine, Gottingen, Germany.

The most frequent genetic subtype of Charcot-Marie-Tooth disease is

CMT1A, linked to chromosome 17p11.2. In the majority of cases, CMT1A

is a gene dosage disease associated with a 1.5 Mb large genomic

duplication.

Transgenic models with extra copies of the Pmp22 gene have provided

formal proof that overexpression of only this candidate gene is

sufficent to cause peripheral demyelination, onion bulb formation,

secondary axonal loss, and progressive muscle atrophy, the

pathological hallmarks of CMT1A.

The transgenic CMT rat with about 1.6-fold PMP22 overexpression

exhibits clinical abnormalities, such as reduced nerve conduction

velocity and lower grip strength that mimick findings in CMT1A

patients. Also transgenic mice, carrying yeast artifical chromosomes

as Pmp22 transgenes, demonstrate the variability of disease

expression as a function of increased gene dosage.

Recently, the first rational experimental therapies of CMT1A were

tested, using transgenic animal models. In one proof-of-principle

study with the CMT rat, a synthetic antagonist of the nuclear

progesterone receptor was shown to reduce PMP22 overexpression and to

ameliorate the clinical severity.

In another study, administration of ascorbic acid, an essential

factor of in vitro myelination, prolonged the survival and restored

myelination of a dysmyelinated mouse model.

Application of gene expression analysis to nerve biopsies that are

readily available from such CMT1A animal models might identify

additional pharmacological targets.