title: Deficiency of dystrophin-associated proteins in Duchenne muscular dystrophy patients lacking COOH-terminal domains of dystrophin.
abstract: Dystrophin, the protein product of the Duchenne muscular dystrophy (DMD) gene, is a cytoskeletal protein tightly associated with a large oligomeric complex of sarcolemmal glycoproteins including dystroglycan, which provides a linkage to the extracellular matrix component, laminin. In DMD, the absence of dystrophin leads to a drastic reduction in all of the dystrophin-associated proteins, causing the disruption of the linkage between the subsarcolemmal cytoskeleton and the extracellular matrix which, in turn, may render muscle cells susceptible to necrosis. The COOH-terminal domains (cysteine-rich and carboxyl-terminal) of dystrophin have been suggested to interact with the sarcolemmal glycoprotein complex. However, truncated dystrophin lacking these domains was reported to be localized to the sarcolemma in four DMD patients recently. Here we report that all of the dystrophin-associated proteins are drastically reduced in the sarcolemma of three DMD patients in whom dystrophin lacking the COOH-terminal domains was properly localized to the sarcolemma. Our results indicate that the COOH-terminal domains of dystrophin are required for the proper interaction of dystrophin with the dystrophin-associated proteins and also support our hypothesis that the loss of the dystrophin-associated proteins in the sarcolemma leads to severe muscular dystrophy even when truncated dystrophin is present in the subsarcolemmal cytoskeleton.
authors.affiliation: Howard Hughes Medical Institute, University of Iowa College of Medicine, Iowa City 52242.
authors.forename: K
authors.initials: K
authors.lastname: Matsumura
authors.forename: F M
authors.initials: FM
authors.lastname: Tomé
authors.forename: V
authors.initials: V
authors.lastname: Ionasescu
authors.forename: J M
authors.initials: JM
authors.lastname: Ervasti
authors.forename: R D
authors.initials: RD
authors.lastname: Anderson
authors.forename: N B
authors.initials: NB
authors.lastname: Romero
authors.forename: D
authors.initials: D
authors.lastname: Simon
authors.forename: D
authors.initials: D
authors.lastname: Récan
authors.forename: J C
authors.initials: JC
authors.lastname: Kaplan
authors.forename: M
authors.initials: M
authors.lastname: Fardeau
mesh_terms: D001706:Biopsy; D002675:Child, Preschool; D016189:Dystrophin / Q000032:analysis / Q000172:deficiency* / Q000235:genetics*; D006801:Humans; D007150:Immunohistochemistry; D007223:Infant; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism; D008961:Models, Structural; D009132:Muscles / Q000378:metabolism* / Q000473:pathology; D009136:Muscular Dystrophies / Q000235:genetics* / Q000473:pathology; D012016:Reference Values; D012508:Sarcolemma / Q000378:metabolism / Q000648:ultrastructure
chemical_list: D016189:Dystrophin; D008562:Membrane Glycoproteins