title: Molecular and genetic characterization of sarcospan: insights into sarcoglycan-sarcospan interactions.
abstract: Autosomal recessive limb girdle muscular dystrophies 2C-2F represent a family of diseases caused by primary mutations in the sarcoglycan genes. We show 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 levels of alpha-, beta- and delta-sarcoglycan. Thus, it is likely that assembly of the complete, tetrameric sarcoglycan complex is a prerequisite for membrane targeting and localization of sarcospan. Based on our findings that sarcospan is integrally associated with the sarcoglycans, we screened >50 autosomal recessive muscular dystrophy cases for mutations in sarcospan. Although we identified three intragenic polymorphisms, we did not find any cases of muscular dystrophy associated with primary mutations in the sarcospan gene. Finally, we have identified an important case of limb girdle muscular dystrophy and cardiomyopathy with normal expression of sarcospan. This patient has a primary mutation in the gamma-sarcoglycan gene, which causes premature truncation of gamma-sarcoglycan without affecting assembly of the mutant gamma-sarcoglycan into a complex with alpha-, beta- and delta-sarcoglycan and sarcospan. This is the first demonstration that membrane expression of a mutant sarcoglycan-sarcospan complex is insufficient in preventing muscular dystrophy and cardiomyopathy and that the C-terminus of gamma-sarcoglycan is critical for the functioning of the entire sarcoglycan-sarcospan complex. These findings are important as they contribute to a greater understanding of the structural determinants required for proper sarcoglycan-sarcospan expression and function.
authors.affiliation: Howard Hughes Medical Institute, Department of Physiology and Biophysics, Department of Neurology, University of Iowa College of Medicine, Iowa City 52242, USA.
authors.forename: R H
authors.initials: RH
authors.lastname: Crosbie
authors.forename: L E
authors.initials: LE
authors.lastname: Lim
authors.forename: S A
authors.initials: SA
authors.lastname: Moore
authors.forename: M
authors.initials: M
authors.lastname: Hirano
authors.forename: A P
authors.initials: AP
authors.lastname: Hays
authors.forename: S W
authors.initials: SW
authors.lastname: Maybaum
authors.forename: H
authors.initials: H
authors.lastname: Collin
authors.forename: S A
authors.initials: SA
authors.lastname: Dovico
authors.forename: C A
authors.initials: CA
authors.lastname: Stolle
authors.forename: M
authors.initials: M
authors.lastname: Fardeau
authors.forename: F M
authors.initials: FM
authors.lastname: Tomé
authors.forename: K P
authors.initials: KP
authors.lastname: Campbell
mesh_terms: D000328:Adult; D009202:Cardiomyopathies / Q000235:genetics / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002869:Chromosome Aberrations / Q000235:genetics* / Q000378:metabolism; D025063:Chromosome Disorders; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism*; D004252:DNA Mutational Analysis; D016189:Dystrophin / Q000378:metabolism*; D005091:Exons; D005260:Female; D005455:Fluorescent Antibody Technique; D005808:Genes, Recessive; D006801:Humans; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D009136:Muscular Dystrophies / Q000235:genetics* / Q000378:metabolism; D009363:Neoplasm Proteins; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D011485:Protein Binding; D049031:Sarcoglycans
chemical_list: D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; D016189:Dystrophin; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D009363:Neoplasm Proteins; C109646:SSPN protein, human; D049031:Sarcoglycans