Mutations that disrupt the carboxyl-terminus of gamma-sarcoglycan cause muscular dystrophy

Recently, mutations in the genes encoding several of the dystrophin-associated proteins have been identified that produce phenotypes rangingfrom severe Duchenne-like autosomal recessive muscular dystrophy to themilder limb-girdle muscular dystrophies (LGMDs). LGMD type 2C is generallyassociated with a more severe clinical course and is prevalent in northernAfrica. A previous study identified a single base pair deletion in the geneencoding the dystrophin-associated protein gamma-sarcoglycan in a number ofTunisian muscular dystrophy patients. To investigate whethergamma-sarcoglycan gene mutations cause autosomal recessive musculardystrophy in other populations, we studied 50 muscular dystrophy patientsfrom the United States and Italy. The muscle biopsies from these 50patients showed no abnormality of dystrophin but did show diminishedimmunostaining for the dystrophin- associated protein alpha-sarcoglycan.Four patients with a severe muscular dystrophy phenotype were identifiedwith homozygous, frameshifting mutations in gamma-sarcoglycan. Two of thefour have microdeletions that disrupt the distal carboxyl-terminus ofgamma- sarcoglycan yet result in a complete absence of gamma-and beta-sarcoglycan suggesting the importance of this region for stability of thesarcoglycan complex. This region of gamma-sarcoglycan, like beta-sarcoglycan, has a number of cysteine residues similar to those inepidermal growth factor cysteine-rich regions.