Loss of the Sarcoglycan Complex and Sarcospan Leads to Muscular Dystrophy in -Sarcoglycan-Deficient Mice

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Abstract
β-Sarcoglycan, one of the subunits of the sarcoglycan complex, is a transmembranous glycoprotein which associates with dystrophin and is the molecule responsible for β-sarcoglycanopathy, a Duchenne-like autosomal recessive muscular dystrophy. To develop an animal model of β-sarcoglycanopathy and to clarify the role of β-sarcoglycan in the pathogenesis of the muscle degeneration in vivo, we developed β-sarcoglycan-deficient mice using a gene targeting technique. β-Sarcoglycan-deficient mice (BSG−/−mice) exhibited progressive muscular dystrophy with extensive degeneration and regeneration. The BSG−/−mice also exhibited muscular hypertrophy characteristic of β-sarcoglycanopathy. Immunohistochemical and immunoblot analyses of BSG−/−mice demonstrated that deficiency of β-sarcoglycan also caused loss of all of the other sarcoglycans as well as of sarcospan in the sarcolemma. On the other hand, laminin-α2, α-and β-dystroglycan and dystrophin were still present in the sarcolemma. However, the dystrophin-dystroglycan complex in BSG−/−mice was unstable compared with that in the wild-type mice. Our data suggest that loss of the sarcoglycan complex and sarcospan alone is sufficient to cause muscular dystrophy, that β-sarcoglycan is an important protein for formation of the sarcoglycan complex associated with sarcospan and that the role of the sarcoglycan complex and sarcospan may be to strengthen the dystrophin axis connecting the basement membrane with the cytoskeleton.