THE DYSTROPHINOPATHIES - AN ALTERNATIVE TO THE STRUCTURAL HYPOTHESIS

Abnormal expression of the cytoskeletal protein dystrophin has deleter ious consequences for skeletal muscle, cardiac muscle, and the central nervous system. A complete failure to express the protein produces Du chenne muscular dystrophy (DMD), in which there is extensive and progr essive skeletal muscle necrosis, the development of a life-threatening dilated cardiomyopathy, and mild mental retardation. Dystrophin binds the F-actin cytoskeleton and is normally expressed in a complex of tr ansmembrane proteins (the ''dystrophin protein complex'') that interac t with external components of the basal lamina. One pathogenic model f or DMD (the ''structural hypothesis'') suggests that this complex form s a structural bridge between the external basal lamina and the intern al cytoskeleton and that the absence of dystrophin produces a defect i n membrane structural support that renders skeletal muscle susceptible to plasmalemmal ruptures (or ''tears'') during the course of contract ile activity. This review attempts to critically evaluate the structur al hypothesis for DMD and presents an opposing model (the ''channel ag gregation model'') that highlights the role of dystrophin in organizin g the membrane cytoskeleton and the role of the cytoskeleton in aggreg ating ion channels and neurotransmitter receptors. Since ion channel a ggregation is a process that is common across organ systems, the idea that channel function can be altered when aggregated ion channels inte ract with a dystrophic cytoskeleton has immediate implications for the expression of the dystrophinopathies in skeletal muscle, cardiac musc le, and the central nervous system. (C) 1998 Academic Press.