Dystrophin-associated protein abnormalities in dystrophin-deficient muscle fibers from symptomatic and asymptomatic Duchenne/Becker muscular dystrophy carriers.
The absence of dystrophin in muscle fibers is associated with a major reduction in dystrophin-associated proteins (DAPs) and disruption of the linkage between the subsarcolemmal cytoskeleton and the extracellular matrix. We investigated the expression of the DAPs beta-dystroglycan, alpha-sarcoglycan, gamma-sarcoglycan and syntrophin as well as utrophin in the muscles of 13 Duchenne muscular dystrophy (DMD) carriers (with variable percentages of dystrophin-deficient fibers and with a range of clinical symptoms), 2 Becker muscular dystrophy (BMD) carriers (expressing a highly truncated protein in some fibers), 2 girls with a DMD-like phenotype, and 11 BMD carriers with almost normal dystrophin expression (reduced or patchy distribution in a few fibers only and rare dystrophin-deficient fibers). DAPs were highly reduced in all fibers lacking dystrophin in the DMD carriers, but were almost normal in the dystrophin-deficient fibers of the 2 BMD carriers with highly truncated dystrophin. In the 11 BMD carriers with nearly normal dystrophin, the few fibers with reduced or patchy dystrophin immunostaining also showed reduced DAP expression in correlation with dystrophin expression. Immunoblot for beta-dystroglycan and alpha-sarcoglycan confirmed the immunohistochemical findings. Utrophin expression was slightly increased in a proportion of fibers in the DMD and BMD carriers with dystrophin mosaicism. We found no correlation between utrophin expression and DAP expression. We conclude that absence or reduction of dystrophin in muscle fibers of DMD and BMD carriers causes a reduction of DAPs in the same fibers, as observed in DMD and BMD patients, while utrophin does not seem to play a role in DAP expression in adult muscle.
Di Blasi
C
C
Department of Neuromuscular Diseases, Istituto Nazionale Neurologico C. Besta, Milan, Italy.
Morandi
L
L
Barresi
R
R
Blasevich
F
F
Cornelio
F
F
Mora
M
M
D000293:Adolescent; D000328:Adult; D000368:Aged; D002135:Calcium-Binding Proteins; D002648:Child; D002675:Child, Preschool; D003598:Cytoskeletal Proteins / Q000032:analysis*; D049030:Dystroglycans; D016189:Dystrophin / Q000031:analogs & derivatives / Q000172:deficiency*; D049029:Dystrophin-Associated Proteins; D005260:Female; D006579:Heterozygote; D006801:Humans; D015151:Immunoblotting; D007223:Infant; D008562:Membrane Glycoproteins / Q000032:analysis*; D008565:Membrane Proteins / Q000032:analysis; D018485:Muscle Fibers, Skeletal / Q000737:chemistry* / Q000187:drug effects*; D009124:Muscle Proteins / Q000032:analysis / Q000276:immunology*; D009136:Muscular Dystrophies / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology*; D049031:Sarcoglycans; D049411:Utrophin
D002135:Calcium-Binding Proteins; D003598:Cytoskeletal Proteins; C483081:DAG1 protein, human; D016189:Dystrophin; D049029:Dystrophin-Associated Proteins; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D009124:Muscle Proteins; D049031:Sarcoglycans; D049411:Utrophin; C091824:syntrophin; C091825:syntrophin alpha1; D049030:Dystroglycans