Deletion of murine SMN exon 7 directed to skeletal muscle leads to severe muscular dystrophy

Spinal muscular atrophy (SMA) is characterized by degeneration of motor neu rons of the spinal cord associated with muscle paralysis and caused by muta tions of the survival motor neuron gene (SMN). To determine whether SMN gen e defect in skeletal muscle might have a role in SMA pathogenesis, deletion of murine SMN exon 7, the most frequent mutation found in SMA, has been re stricted to skeletal muscle by using the Cre-loxP system. Mutant mice displ ay ongoing muscle necrosis with a dystrophic phenotype leading to muscle pa ralysis and death. The dystrophic phenotype is associated with elevated lev els of creatine kinase activity, Evans blue dye uptake into muscle fibers, reduced amount of dystrophin and upregulation of utrophin expression sugges ting a destabilization of the sarcolemma components. The mutant mice will b e a valuable model for elucidating the underlying mechanism. Moreover, our results suggest a primary involvement of skeletal muscle in human SMA, whic h may contribute to motor defect in addition to muscle denervation caused b y the motor neuron degeneration. These data may have important implications for the development of therapeutic strategies in SMA.