CMT 1B: R69C Knockin Mice Provide a Gain of Function Model for Early Onset CMT

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R69C Knockin Mice Provide a Gain of Function Model for Early Onset

CMT1B

(ANN April 17, 2008)

R. Shy, Cinzia Ferri, Cherie Southwood, Pennuto, Jun Li,

Xingyao Wu, L. Feltri, Larry Wrabetz, Milan, Italy, Gow,

E. Shy, Detroit, MI

OBJECTIVE: To generate a knockin mouse model of early onset Charcot

Marie Tooth disease 1B (CMT1B).

BACKGROUND: Mutations in myelin protein zero (MPZ) cause CMT1B. Many

MPZ mutations, including R69C, present as infantile onset

dysmyelinating neuropathies with NCV < 15 m/sec. We wish to generate

an animal model of early onset CMT1B to investigate the pathogenesis

and develop therapies for CMT1B.

DESIGN/METHODS: Cre-lox techniques knocked-in (KI) the R69C

mutation into the Mpz gene of mice that were analyzed by clinical,

neurophysiological, morphological, and molecular techniques. RESULTS:

Heterozygous KI mice had NCV of 10-15 m/sec at two months of age and

abnormally thin myelin that rarely surpassed 0.6 m even when

ensheathing large diameter axons. Homozygous R69C KI mice had a

severe clinical phenotype characterized by tremor and limb weakness

identifiable during weaning, NCV of 3 m/sec and morphological

analysis revealed severe dysmyelination. Western blot demonstrated

reduced levels for myelin specific genes in both heterozygous and

homozygous mice. Preliminary studies suggest that MPZ is retained in

the cytoplasm in all mutant mice, however, we have not seen evidence

of apoptosis or activation of the UPR.

CONCLUSIONS/RELEVANCE: The R69C mutation introduces a toxic gain of

function that arrests myelin development in homozygous mice and

disrupts axonal-SC interactions in heterozygous animals. R69C knockin

mice are appropriate models to investigate early onset CMT1B.