Disruption of the beta-sarcoglycan gene reveals pathogenetic complexity of limb-girdle muscular dystrophy type 2E.
Limb-girdle muscular dystrophy type 2E (LGMD 2E) is caused by mutations in the beta-sarcoglycan gene, which is expressed in skeletal, cardiac, and smooth muscle. beta-sarcoglycan-deficient (Sgcb-null) mice developed severe muscular dystrophy and cardiomyopathy with focal areas of necrosis. The sarcoglycan-sarcospan and dystroglycan complexes were disrupted in skeletal, cardiac, and smooth muscle membranes. epsilon-sarcoglycan was also reduced in membrane preparations of striated and smooth muscle. Loss of the sarcoglycan-sarcospan complex in vascular smooth muscle resulted in vascular irregularities in heart, diaphragm, and kidneys. Further biochemical characterization suggested the presence of a distinct epsilon-sarcoglycan complex in skeletal muscle that was disrupted in Sgcb-null mice. Thus, perturbation of vascular function together with disruption of the epsilon-sarcoglycan-containing complex represents a novel mechanism in the pathogenesis of LGMD 2E.
Durbeej
M
M
Howard Hughes Medical Institute, Department of Physiology and Biophysics, University of Iowa College of Medicine, Iowa City 52242, USA.
Cohn
R D
RD
Hrstka
R F
RF
Moore
S A
SA
Allamand
V
V
Davidson
B L
BL
Williamson
R A
RA
Campbell
K P
KP
D000818:Animals; D009202:Cardiomyopathies / Q000235:genetics / Q000473:pathology; D003598:Cytoskeletal Proteins / Q000172:deficiency / Q000235:genetics* / Q000502:physiology; D049030:Dystroglycans; D016189:Dystrophin / Q000235:genetics; D008168:Lung / Q000473:pathology; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000235:genetics* / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D008861:Microsomes / Q000473:pathology; D018482:Muscle, Skeletal / Q000473:pathology*; D009137:Muscular Dystrophy, Animal / Q000235:genetics* / Q000473:pathology*; D009206:Myocardium / Q000473:pathology*; D009336:Necrosis
D003598:Cytoskeletal Proteins; D016189:Dystrophin; D008562:Membrane Glycoproteins; D049030:Dystroglycans