MUTATIONS THAT DISRUPT THE CARBOXYL-TERMINUS OF GAMMA-SARCOGLYCAN CAUSE MUSCULAR-DYSTROPHY

Recently, mutations in the genes encoding several of the dystrophin-as sociated proteins have been identified that produce phenotypes ranging from severe Duchenne-like autosomal recessive muscular dystrophy to t he milder limb-girdle muscular dystrophies (LGMDs). LGMD type 2C is ge nerally associated with a more severe clinical course and is prevalent in northern Africa. A previous study identified a single base pair de letion in the gene encoding the dystrophin-associated protein gamma-sa rcoglycan in a number of Tunisian muscular dystrophy patients. To inve stigate whether gamma-sarcoglycan gene mutations cause autosomal reces sive muscular dystrophy in other populations, we studied 50 muscular d ystrophy patients from the United States and Italy. The muscle biopsie s from these 50 patients showed no abnormality of dystrophin but did s how diminished immunostaining for the dystrophin-associated protein al pha-sarcoglycan. Four patients with a severe muscular dystrophy phenot ype were identified with homozygous, frameshifting mutations in gamma- sarcoglycan. Two of the four have microdeletions that disrupt the dist al carboxyl-terminus of gamma-sarcoglycan yet result in a complete abs ence of gamma- and beta-sarcoglycan suggesting the importance of this region for stability of the sarcoglycan complex, This region of gamma- sarcoglycan, like beta-sarcoglycan, has a number of cysteine residues similar to those in epidermal growth factor cysteine-rich regions.