title: Progressive muscular dystrophy in alpha-sarcoglycan-deficient mice.
abstract: Limb-girdle muscular dystrophy type 2D (LGMD 2D) is an autosomal recessive disorder caused by mutations in the alpha-sarcoglycan gene. To determine how alpha-sarcoglycan deficiency leads to muscle fiber degeneration, we generated and analyzed alpha-sarcoglycan- deficient mice. Sgca-null mice developed progressive muscular dystrophy and, in contrast to other animal models for muscular dystrophy, showed ongoing muscle necrosis with age, a hallmark of the human disease. Sgca-null mice also revealed loss of sarcolemmal integrity, elevated serum levels of muscle enzymes, increased muscle masses, and changes in the generation of absolute force. Molecular analysis of Sgca-null mice demonstrated that the absence of alpha-sarcoglycan resulted in the complete loss of the sarcoglycan complex, sarcospan, and a disruption of alpha-dystroglycan association with membranes. In contrast, no change in the expression of epsilon-sarcoglycan (alpha-sarcoglycan homologue) was observed. Recombinant alpha-sarcoglycan adenovirus injection into Sgca-deficient muscles restored the sarcoglycan complex and sarcospan to the membrane. We propose that the sarcoglycan-sarcospan complex is requisite for stable association of alpha-dystroglycan with the sarcolemma. The Sgca-deficient mice will be a valuable model for elucidating the pathogenesis of sarcoglycan deficient limb-girdle muscular dystrophies and for the development of therapeutic strategies for this disease.
authors.affiliation: Howard Hughes Medical Institute, Department of Physiology and Biophysics and Department of Neurology, University of Iowa College of Medicine, Iowa City, Iowa 52242-1101, USA.
authors.forename: F
authors.initials: F
authors.lastname: Duclos
authors.forename: V
authors.initials: V
authors.lastname: Straub
authors.forename: S A
authors.initials: SA
authors.lastname: Moore
authors.forename: D P
authors.initials: DP
authors.lastname: Venzke
authors.forename: R F
authors.initials: RF
authors.lastname: Hrstka
authors.forename: R H
authors.initials: RH
authors.lastname: Crosbie
authors.forename: M
authors.initials: M
authors.lastname: Durbeej
authors.forename: C S
authors.initials: CS
authors.lastname: Lebakken
authors.forename: A J
authors.initials: AJ
authors.lastname: Ettinger
authors.forename: J
authors.initials: J
authors.lastname: van der Meulen
authors.forename: K H
authors.initials: KH
authors.lastname: Holt
authors.forename: L E
authors.initials: LE
authors.lastname: Lim
authors.forename: J R
authors.initials: JR
authors.lastname: Sanes
authors.forename: B L
authors.initials: BL
authors.lastname: Davidson
authors.forename: J A
authors.initials: JA
authors.lastname: Faulkner
authors.forename: R
authors.initials: R
authors.lastname: Williamson
authors.forename: K P
authors.initials: KP
authors.lastname: Campbell
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002352:Carrier Proteins / Q000096:biosynthesis / Q000502:physiology; D003598:Cytoskeletal Proteins / Q000172:deficiency* / Q000235:genetics; D018076:DNA, Complementary; D018450:Disease Progression; D016189:Dystrophin / Q000378:metabolism; D018014:Gene Transfer Techniques; D006023:Glycoproteins / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000172:deficiency* / Q000235:genetics; D008565:Membrane Proteins / Q000096:biosynthesis / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D009119:Muscle Contraction; D009137:Muscular Dystrophy, Animal / Q000209:etiology* / Q000503:physiopathology; D009363:Neoplasm Proteins; D049031:Sarcoglycans; D012508:Sarcolemma / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; D018076:DNA, Complementary; D016189:Dystrophin; D006023:Glycoproteins; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D049031:Sarcoglycans; C491632:Sspn protein, mouse