A transgenic animal model for CMT disease caused by mutations in HSPBl shows len

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A transgenic animal model for Charcot-Marie-Tooth disease caused by mutations in

HSPBl shows length-dependent muscle weakening and atrophy due to axonal loss.

C. d'Ydewallel ,2, J. Krishnanl ,2, P. Van Dammel ,2, W. Robbereche,2 and L. Van

Den Bosch1,2 lVesalius Research Center, VIB and University of Leuven, Leuven,

Belgium; 2LaboratOIY of Neurobiology,

Division of Clinical and Experimental Neurology, Department of Neurosciences,

University of Leuven, Leuven, Belgium

Charcot-Mamie-Tooth (CMT) disease is the most cornmon inherited disorder of the

peripheral nervous system affecting 1:2500 individuals. Clinically, CMT patients

show slowly progressing distal muscle weakening and atrophy, foot deformities,

steppage gait, sensory

loss and decreased/absent deep tendon reflexes.

Electrophysiologically, CMT is classified into three groups: demyelinating CMT

(type 1), CMT characterized by axonal loss (type 2),

and spinal forms. In the latter, exclusively lower motor neurons are affected;

hence, they are referred to as distal hereditmy motor neuropathies (dHMN) Thus

far, CMT has been associated with 40 known causative genes.

Previously, the gene encoding small heat shock protein (HSPBl) has been

identified as the defective gene causing CMT2F (OMIM 606595)

So fm, 11 missense mutations have been identified in HSPB1 which me all

associated to CMT2.

To elucidate the exact pathological mechanism underlying CMT2F in vivo, we

developed and characterized transgenic mice expressing human wildtype or mutant

HSPB1 driven by a Thyl.2 expression cassette. Western blot analysis confirmed

the neuronal specificity of HSPB1 expression and indicated a 3- to 5-fold

increase in protein level

compared to endogenous Hsp25 Mutallt HSPB1 expressing mice mimic key features of

CMT2 including length-dependent weakening and atrophy of muscles starting at the

age of 6 months Moreover, signs of chronic denervation with mild reinnervation

were observed in muscle biopsy.

This process was also observed in sciatic nelves. Furthermore, mutant HSPB1

expressing mice showed all altered gait pattern. Nerve conduction strrdies

demonstrated decreased amplitudes of both CMAPs and SNAPs while latencies were

unaffected. These observations confirm axonal loss in both motor and sensory

nemons as being the primary

cause of the phenotype.

This work describes a new mouse model for CMT2. Moreover, this

model provides a tool to elucidate the pathological mechanism underlying CMT2

eventually paving the way to develop therapeutical strategies for peripheral

neuropathies.