Assembly of the sarcoglycan complex. Insights for muscular dystrophy

Abstract

Four unique transmembrane glycoproteins comprise the sarcoglycan complex in striated muscle. The sarcoglycan complex contributes to maintenance of sarcolemma integrity. A shared feature of four types of autosomal recessive limb girdle muscular dystrophy (LGMD) is that mutations in a single sarcoglycan gene result in the loss of all sarcoglycans at the sarcolemma. The mechanism of destabilization is unknown. We report here our findings of sarcoglycan complex biosynthesis in a heterologous cell system. We demonstrate that the sarcoglycans are glycosylated and assemble into a complex that resides in the plasma membrane. Complex assembly was dependent on the simultaneous synthesis of all four sarcoglycans. Mutant sarcoglycans block complex formation and insertion of the sarcoglycans into the plasma membrane. This constitutes the first biochemical evidence to support the idea that the molecular defect in sarcoglycan-deficient LGMD is because of aberrant sarcoglycan complex assembly and trafficking, which leads to the absence of the complex from the sarcolemma.