An Animal Model for CMT Type 4B1 using embryonic stem cell technology

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Hum Mol Genet. 2005 Oct 25

An Animal Model for Charcot-Marie-Tooth Disease Type 4B1 (CMT4B1).

Bonneick S, Boentert M, Berger P, Atanasoski S, Mantei N, Wessig C,

Toyka KV, Young P, Suter U.

Institute of Cell Biology, Department of Biology, Swiss Federal

Institute of Technology, ETH-Honggerberg, Zurich, Switzerland.

Charcot-Marie-Tooth disease (CMT) comprises a family of clinically

and genetically very heterogeneous hereditary peripheral

neuropathies, and is one of the most common inherited neurological

disorders. We have generated a mouse model for CMT type 4B1 using

embryonic stem cell technology.

To this end, we introduced a stop codon into the Mtmr2 locus within

exon 9, at the position encoding amino acid 276 of the MTMR2 protein

(E276X). Concomitantly, we have deleted the chromosomal region

immediately downstream of the stop codon up to within exon 13. The

resulting allele closely mimics the mutation found in a Saudi Arabian

CMT4B1 patient.

Animals homozygous for the mutation showed various degrees of complex

myelin infoldings and outfoldings exclusively in peripheral nerves,

in agreement with CMT4B1 genetics and pathology. Mainly paranodal

regions of the myelin sheath were affected, with a high degree of

quantitative and qualitative variability between individuals. This

pathology was progressive with age and axonal damage was occasionally

observed. Distal nerve regions were more affected than proximal

parts, in line with the distribution in CMT.

However, we found no significant electrophysiological changes, even

in aged (16 month-old) mice, suggesting that myelin infoldings and

outfoldings per se are not invariably associated with detectable

electrophysiological abnormalities.

Our animal model provides a basis for future detailed molecular and

cellular studies on the underlying disease mechanisms in CMT4B1. Such

an analysis will reveal how the disease develops, in particular the

enigmatic myelin infoldings and outfoldings as well as axonal damage,

and provide mechanistic insights that may aid in the development of

potential therapeutic approaches.