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The dystrophin glycoprotein complex (DGC) is found at the plasma membrane of muscle cells, where it provides a link between the cytoskeleton and the extracellular matrix. A subcomplex within the DGC, the sarcoglycan complex, associates with dystrophin and mediates muscle membrane stability. Mutations in sarcoglycan genes lead to muscular dystrophy and cardiomyopathy in both humans and mice. In invertebrates, there are three sarcoglycan genes, while in mammals there are additional sarcoglycan genes that probably arose from gene duplication events. We identified a novel mammalian sarcoglycan, ζ-sarcoglycan, that is highly related to γ-sarcoglycan and δ-sarcoglycan. We generated a ζ-sarcoglycan-specific antibody and found that ζ-sarcoglycan associated with other members of the sarcoglycan complex at the plasma membrane. Additionally, ζ-sarcoglycan was reduced at the membrane in muscular dystrophy, consistent with a role in mediating membrane stability. ζ-Sarcoglycan was also found as a component of the vascular smooth muscle sarcoglycan complex. Together, these data demonstrate that ζ-sarcoglycan is an integral component of the sarcoglycan complex and, as such, is important in the pathogenesis of muscular dystrophy.

ζ-Sarcoglycan, a novel component of the sarcoglycan complex, is reduced in muscular dystrophy