Type 1B severe/early onset - research from Germany

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Research from J Cell Biol. May 17 2004

Pathology of a mouse mutation in peripheral myelin protein P0 is

characteristic of a severe and early onset form of human

Charcot-Marie-Tooth type 1B disorder.

Runker AE, Kobsar I, Fink T, Loers G, Tilling T, Putthoff P, Wessig C,

i R, Schachner M.

Zentrum fur Molekulare Neurobiologie, Universitat Hamburg, istr.

52, D-20246 Hamburg, Germany.

Mutations in the gene of the peripheral myelin protein zero (P0) give

rise to the peripheral neuropathies Charcot-Marie-Tooth type 1B disease

(CMT1B), Dejerine-Sottas syndrome, and congenital hypomyelinating

neuropathy. To investigate the pathomechanisms of a specific point

mutation in the P0 gene, we generated two independent transgenic mouse

lines expressing the pathogenic CMT1B missense mutation Ile106Leu

(P0sub) under the control of the P0 promoter on a wild-type background.

Both P0sub-transgenic mouse lines showed shivering and ultrastructural

abnormalities including retarded myelination, onion bulb formation, and

dysmyelination seen as aberrantly folded myelin sheaths and tomacula in

all nerve fibers. Functionally, the mutation leads to dispersed compound

muscle action potentials and severely reduced conduction velocities. Our

observations support the view that the Ile106Leu mutation acts by a

dominant-negative gain of function and that the P0sub-transgenic mouse

represents an animal model for a severe, tomaculous form of CMT1B.