title: Mutations that disrupt the carboxyl-terminus of gamma-sarcoglycan cause muscular dystrophy.
abstract: Recently, mutations in the genes encoding several of the dystrophin-associated proteins have been identified that produce phenotypes ranging from severe Duchenne-like autosomal recessive muscular dystrophy to the milder limb-girdle muscular dystrophies (LGMDs). LGMD type 2C is generally associated with a more severe clinical course and is prevalent in northern Africa. A previous study identified a single base pair deletion in the gene encoding the dystrophin-associated protein gamma-sarcoglycan in a number of Tunisian muscular dystrophy patients. To investigate whether gamma-sarcoglycan gene mutations cause autosomal recessive muscular dystrophy in other populations, we studied 50 muscular dystrophy patients from the United States and Italy. The muscle biopsies from these 50 patients showed no abnormality of dystrophin but did show diminished immunostaining for the dystrophin-associated protein alpha-sarcoglycan. Four patients with a severe muscular dystrophy phenotype were identified with homozygous, frameshifting mutations in gamma-sarcoglycan. Two of the four have microdeletions that disrupt the distal carboxyl-terminus of gamma-sarcoglycan yet result in a complete absence 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.
authors.affiliation: Division of Genetics, Children's Hospital, Boston, MA 02115, USA.
authors.forename: E M
authors.initials: EM
authors.lastname: McNally
authors.forename: D
authors.initials: D
authors.lastname: Duggan
authors.forename: J R
authors.initials: JR
authors.lastname: Gorospe
authors.forename: C G
authors.initials: CG
authors.lastname: Bönnemann
authors.forename: M
authors.initials: M
authors.lastname: Fanin
authors.forename: E
authors.initials: E
authors.lastname: Pegoraro
authors.forename: H G
authors.initials: HG
authors.lastname: Lidov
authors.forename: S
authors.initials: S
authors.lastname: Noguchi
authors.forename: E
authors.initials: E
authors.lastname: Ozawa
authors.forename: R S
authors.initials: RS
authors.lastname: Finkel
authors.forename: R P
authors.initials: RP
authors.lastname: Cruse
authors.forename: C
authors.initials: C
authors.lastname: Angelini
authors.forename: L M
authors.initials: LM
authors.lastname: Kunkel
authors.forename: E P
authors.initials: EP
authors.lastname: Hoffman
mesh_terms: D000595:Amino Acid Sequence; D002648:Child; D003598:Cytoskeletal Proteins; D016189:Dystrophin / Q000032:analysis; D016368:Frameshift Mutation / Q000235:genetics; D005808:Genes, Recessive / Q000235:genetics; D006720:Homozygote; D006801:Humans; D066298:In Vitro Techniques; D007558:Italy; D008297:Male; D008562:Membrane Glycoproteins / Q000032:analysis / Q000235:genetics*; D008969:Molecular Sequence Data; D018482:Muscle, Skeletal / Q000737:chemistry; D009136:Muscular Dystrophies / Q000235:genetics* / Q000503:physiopathology; D009154:Mutation / Q000235:genetics*; D018807:Polymorphism, Single-Stranded Conformational; D049031:Sarcoglycans; D017384:Sequence Deletion / Q000235:genetics; D017386:Sequence Homology, Amino Acid; D014481:United States
chemical_list: D003598:Cytoskeletal Proteins; D016189:Dystrophin; D008562:Membrane Glycoproteins; D049031:Sarcoglycans