Molecular and genetic characterization of sarcospan: insights into sarcoglycan-sarcospan interactions

Autosomal recessive limb girdle muscular dystrophies 2C-2F represent a fami ly of diseases caused by primary mutations in the sarcoglycan genes. We sho w that sarcospan, a novel tetraspan-like protein, is also lost in patients with either a complete or partial loss of the sarcoglycans. In particular, sarcospan was absent in a gamma-sarcoglycanopathy patient with normal level s of alpha-, beta- and delta-sarcoglycan, Thus, it is likely that assembly of the complete, tetrameric sarcoglycan complex is a prerequisite for membr ane targeting and localization of sarcospan, Based on our findings that sar cospan is integrally associated with the sarcoglycans, we screened >50 auto somal recessive muscular dystrophy cases for mutations in sarcospan, Althou gh we identified three intragenic polymorphisms, we did not find any cases of muscular dystrophy associated with primary mutations in the sarcospan ge ne. Finally, we have identified an important case of limb girdle muscular d ystrophy and cardiomyopathy with normal expression of sarcospan. This patie nt has a primary mutation in the gamma-sarcoglycan gene, which causes prema ture truncation of gamma-sarcoglycan without affecting assembly of the muta nt gamma-sarcoglycan into a complex with alpha-, beta- and delta-sarcoglyca n and sarcospan, This is the first demonstration that membrane expression o f a mutant sarcoglycan-sarcospan complex is insufficient in preventing musc ular dystrophy and cardiomyopathy and that the C-terminus of gamma-sarcogly can is critical for the functioning of the entire sarcoglycan-sarcospan com plex. These findings are important as they contribute to a greater understa nding of the structural determinants required for proper sarcoglycan-sarcos pan expression and function.