Deletion of Murine SMN Exon 7 Directed to Skeletal Muscle Leads to Severe Muscular Dystrophy

• Published in: The Journal of cell biology Vol. 152; no. 5; pp. 1107 - 1114
• Main Authors: Cifuentes-Diaz, Carmen, Frugier, Tony, Tiziano, Francesco D., Lacène, Emmanuelle, Roblot, Natacha, Joshi, Vandana, Moreau, Marie Helene, Melki, Judith
• Format: Journal Article
• Language: English
• Published: United States Rockefeller University Press 05.03.2001; The Rockefeller University Press
• Subjects: Animals; Antibodies; Biomarkers; Cell Size; Creatine Kinase - metabolism; Cyclic AMP Response Element-Binding Protein; Cytoskeletal Proteins - metabolism; Dystrophin - metabolism; Dystrophy; Evans Blue - metabolism; Exons; Exons - genetics; Fluorescent Antibody Technique; Genes; Histology; Membrane Proteins - metabolism; Mice; Motor neurons; Motor Neurons - metabolism; Motor Neurons - pathology; Muscle fibers; Muscle Fibers, Skeletal - metabolism; Muscle Fibers, Skeletal - pathology; Muscle, Skeletal - metabolism; Muscle, Skeletal - pathology; Muscles; Muscular Atrophy, Spinal - genetics; Muscular Dystrophies - enzymology; Muscular Dystrophies - metabolism; Muscular Dystrophies - pathology; Muscular dystrophy; Muscular system; Mutation; Nerve Tissue Proteins - genetics; Neuromuscular Junction - metabolism; Neurons; Paralysis; RNA-Binding Proteins; Sarcolemma - metabolism; Sarcolemma - pathology; Sequence Deletion - genetics; Skeletal muscle; Skeletal system; SMN Complex Proteins; SMN gene; Spinal muscular atrophy; Utrophin
• ISSN: 0021-9525; 1540-8140
• DOI: 10.1083/jcb.152.5.1107

Spinal muscular atrophy (SMA) is characterized by degeneration of motor neurons of the spinal cord associated with muscle paralysis and caused by mutations of the survival motor neuron gene (SMN). To determine whether SMN gene 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 restricted to skeletal muscle by using the Cre-loxP system. Mutant mice display ongoing muscle necrosis with a dystrophic phenotype leading to muscle paralysis and death. The dystrophic phenotype is associated with elevated levels of creatine kinase activity, Evans blue dye uptake into muscle fibers, reduced amount of dystrophin and upregulation of utrophin expression suggesting a destabilization of the sarcolemma components. The mutant mice will be a valuable model for elucidating the underlying mechanism. Moreover, our results suggest a primary involvement of skeletal muscle in human SMA, which may contribute to motor defect in addition to muscle denervation caused by the motor neuron degeneration. These data may have important implications for the development of therapeutic strategies in SMA.