ABSTRACT
Duchenne muscular dystrophy (DMD) and the allelic Becker muscular dystrophy (BMD) are X-linked recessive disorders caused by mutations in the dystrophin gene. The dystrophin gene spans 2.4 MB on the human X-chromosome and contains seven promoters, each with a unique first exon, and 78 additional coding exons. Despite years of study, the function of this protein is not completely understood, and it appears to serve slightly different roles in muscle and nonmuscle tissues. This chapter will focus on the role of dystrophin in muscle, where it is thought to be a structural protein providing a flexible and elastic link between the cortical actin cytoskeleton and the extracellular matrix via interactions with the dystrophin-glycoprotein complex. This link helps to dissipate muscle contractile force from the intracellular cytoskeleton to the extracellular matrix. The absence of dystrophin disrupts this link, resulting in membrane fragility and rendering the sarcolemma susceptible to me chanical injury during contraction. The absence of dystrophin also results in destabilization of the DGC. Loss of the DGC, combined with transient disruptions of sarcolemma integrity, leads to myofiber necrosis by mechanisms that are poorly understood. Some of the proteins that interact with dystrophin, particularly certain components of the DGC, appear to be in volved in signaling cascades. Consequently, a complete understanding of the function of dystrophin requires consideration of its direct structural role as well as its indirect role in local izing signaling molecules.
