title: Functional rescue of the sarcoglycan complex in the BIO 14.6 hamster using delta-sarcoglycan gene transfer.
abstract: Four types of limb-girdle muscular dystrophy (LGMD) are known to be caused by mutations in distinct sarcoglycan genes. The BIO 14.6 hamster is a model for sarcoglycan-deficient LGMD with a deletion in the delta-sarcoglycan (delta-SG) gene. We investigated the function of the sarcoglycan complex and the feasibility of sarcoglycan gene transfer for LGMD using a recombinant delta-SG adenovirus in the BIO 14.6 hamster. We demonstrate extensive long-term expression of delta-sarcoglycan and rescue of the entire sarcoglycan complex, as well as restored stable association of alpha-dystroglycan with the sarcolemma. Importantly, muscle fibers expressing delta-sarcoglycan lack morphological markers of muscular dystrophy and exhibit restored plasma membrane integrity. In summary, the sarcoglycan complex is requisite for the maintenance of sarcolemmal integrity, and primary mutations in individual sarcoglycan components can be corrected in vivo.
authors.affiliation: Howard Hughes Medical Institute, Department of Physiology and Biophysics, University of Iowa College of Medicine, Iowa City, Iowa 52242, USA.
authors.forename: K H
authors.initials: KH
authors.lastname: Holt
authors.forename: L E
authors.initials: LE
authors.lastname: Lim
authors.forename: V
authors.initials: V
authors.lastname: Straub
authors.forename: D P
authors.initials: DP
authors.lastname: Venzke
authors.forename: F
authors.initials: F
authors.lastname: Duclos
authors.forename: R D
authors.initials: RD
authors.lastname: Anderson
authors.forename: B L
authors.initials: BL
authors.lastname: Davidson
authors.forename: K P
authors.initials: KP
authors.lastname: Campbell
mesh_terms: D000256:Adenoviridae; D000818:Animals; D006224:Cricetinae; D003598:Cytoskeletal Proteins / Q000235:genetics*; D018014:Gene Transfer Techniques; D006801:Humans; D007273:Injections, Intramuscular; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics*; D008845:Microinjections; D018485:Muscle Fibers, Skeletal / Q000737:chemistry / Q000502:physiology; D018482:Muscle, Skeletal / Q000737:chemistry / Q000166:cytology / Q000503:physiopathology; D009137:Muscular Dystrophy, Animal / Q000235:genetics* / Q000628:therapy*; D009154:Mutation / Q000502:physiology; D010957:Plasmids / Q000494:pharmacology; D011994:Recombinant Proteins / Q000494:pharmacology; D049031:Sarcoglycans; D012508:Sarcolemma / Q000502:physiology
chemical_list: D003598:Cytoskeletal Proteins; D008562:Membrane Glycoproteins; D011994:Recombinant Proteins; D049031:Sarcoglycans