Type 2A: Hindlimb gait defects due to motor axon loss and reduced distal muscles

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Human Molecular Genetics Advance Access published online on October

24, 2007

Hindlimb gait defects due to motor axon loss and reduced distal

muscles in a transgenic mouse model of Charcot-Marie-Tooth type 2A

A. Detmer1, Vande Velde2, Don W. Cleveland2 and

C. Chan1,*

1 Division of Biology California Institute of Technology 1200 East

California Blvd, MC114-96 Pasadena, CA 91125 2 Ludwig Institute

University of California, San Diego 9500 Gilman Drive La Jolla, CA

92093

Charcot-Marie-Tooth (CMT) disease type 2A is a progressive,

neurodegenerative disorder affecting long peripheral motor and

sensory nerves. The most common clinical sign is weakness in the

lower legs and feet, associated with muscle atrophy and gait

defects. The axonopathy in CMT2A is caused by mutations in Mitofusin

2 (Mfn2), a mitochondrial GTPase necessary for the fusion of

mitochondria. Most Mfn2 disease alleles dominantly aggregate

mitochondria upon expression in cultured fibroblasts and neurons. To

determine whether this property is related to neuronal pathogenesis,

we used the HB9 promoter to drive expression of a pathogenic allele,

Mfn2T105M, in the motor neurons of transgenic mice. Transgenic mice

develop key clinical signs of CMT2A disease in a dosage-dependent

manner. They have a severe gait defect due to an inability to dorsi-

flex the hindpaws.

Consequently, affected animals drag their hindpaws while walking and

support themselves on the hind knuckles, rather than the soles. This

distal muscle weakness is associated with reduced numbers of motor

axons in the motor roots and severe reduction of the anterior calf

muscles. Many motor neurons from affected animals show improper

mitochondrial distribution, characterized by tight clusters of

mitochondria within axons. This transgenic line recapitulates key

motor features of CMT2A and provides a system to dissect the

function of mitochondria in the axons of mammalian motor neurons.