The function of the SG-SSPN subcomplex is to stabilize ␣-DG at the sarcolemma Durbeej et al., 2000;Holt et al., 1998;Straub et al., 1998), thereby completing the linkage between the extracellular matrix and the F-actin cytoskeleton (Ervasti and Campbell, 1993). Disruption of this linkage renders the sarcolemma susceptible to contractioninduced damage (Petrof et al., 1993). SSPN is absent from the sarcolemma of patients with sarcoglycan-deficient AR-LGMD, indicating that membrane targeting and stability of SSPN is dependent on the SGs (Crosbie et al., 1999). Sarcospan is not restored to the sarcolemma even in AR-LGMD cases with partial SG deficiency where three out of four The dystrophin-glycoprotein complex spans the muscle plasma membrane and provides a mechanical linkage between laminin in the extracellular matrix and actin in the intracellular cytoskeleton. Within the dystrophinglycoprotein complex, the sarcoglycans and sarcospan constitute a subcomplex of transmembrane proteins that stabilize ␣-dystroglycan, a receptor for laminin and other components of the extracellular matrix. In order to elucidate the function of sarcospan, we generated transgenic mice that overexpress sarcospan in skeletal muscle. Sarcospan transgenic mice with moderate (tenfold) levels of sarcospan overexpression exhibit a severe phenotype that is similar to mouse models of laminindeficient congenital muscular dystrophy (MD). Sarcospan transgenic mice display severe kyphosis and die prematurely between 6 and 10 weeks of age. Histological analysis reveals that sarcospan expression causes muscle pathology marked by increased muscle fiber degeneration and/or regeneration. Sarcospan transgenic muscle does not display sarcolemma damage, which is distinct from dystrophin-and sarcoglycan-deficient muscular dystrophies. We show that sarcospan clusters the sarcoglycans into insoluble protein aggregates and causes destabilization of ␣-dystroglycan. Evidence is provided to demonstrate abnormal extracellular matrix assembly, which represents a probable pathological mechanism for the severe and lethal dystrophic phenotype. Taken together, these **data** suggest that sarcospan plays an important mechanical role in stabilizing the dystrophin-glycoprotein complex.