Role of dystrophin isoforms and associated proteins in muscular dystrophy (Review)

The membrane cytoskeletal component dystrophin and its associated glycoprot eins play a central role in the molecular pathogenesis of several muscular dystrophies, i.e. Duchenne/Becker muscular dystrophy, congenital muscular d ystrophy and various forms of limb-girdle muscular dystrophy. Although the most frequent of these disorders, Duchenne muscular dystrophy, is mainly re cognized as a disease of skeletal muscle fibers, pathophysiological changes also involve the heart and diaphragm, as well as the peripheral and centra l nervous system. Thus current research efforts into the elucidation of the molecular mechanisms underlying these genetic diseases are not only direct ed towards studying skeletal muscle necrosis but also investigate abnormali ties of heart and brain dystrophin-glycoprotein complexes in cardiomyopathy and brain deficiencies associated with muscular dystrophy. Furthermore, ma ny isoforms of dystrophin and dystrophin-associated components have been id entified in various non-muscle tissues and their function(s) are mostly unk nown. With respect to skeletal muscle fibers, the characterization of new d ystrophin-associated proteins, such as dystrobrevin, sarcospan and the synt rophins, led to a modified model of the spatial configuration of the dystro phin-glycoprotein complex. However, it is generally accepted now that beta- dystroglycan forms the plasmalemma-spanning linkage between dystrophin and the laminin-binding protein alpha-dystroglycan and that this complex is ass ociated with the sarcoglycan subcomplex of sarcolemmal glycoproteins.