ABSTRACT
The obstacles to gene therapy approaches in the treatment of Duchenne muscular dystrophy (DMD), as outlined in several chapters in this book (see Chapters 17-19), have led to many investigations to seek alternative therapeutic strategies. One of the hurdles to non-genetic therapy for DMD is the absence of a well-defined pathogenetic process leading from
dystrophin deficiency to the pathological manifestations of DMD. The ‘‘function’’ of dystrophin is deduced primarily by what is observed in its absence, but this is complicated by the fact that the histological phenotype of dystrophin-deficiency can vary widely. Dystrophin-deficient muscle displays normal or nearly normal histology in very young dystrophin-deficient (mdx) mice and in certain muscle groups in both DMD patients and animal models (1-3). It appears predominantly hypertrophic in the feline model (4), it displays mild degenerative changes in specific cases in humans (5), and it displays severe degenerative changes in human limb and trunk muscles in typical DMD patients (6). Understanding the function of dystrophin by the examination of dystrophin-deficient muscle is further complicated by the fact that dystrophin is part of a multicomponent protein complex, generally referred to as the dystrophin-associated protein complex (DAPC) or more narrowly as the dystrophin-glycoprotein complex (7-9). This complex includes, at its core, the transmembrane dystroglycan complex (a heterodimer composed of a transmembrane b-subunit and an extracellular a-subunit) that binds dystrophin intracellularly and laminin extracellularly (10). The sarcoglycan complex likewise is a transmembrane protein complex tightly associated with the dystroglycan complex (11). Intracellularly, dystrophin and b-dystroglycan bind to numerous other proteins including, directly or indirectly, actin, dystrobrevins, and syntrophins (7-9). Dystrophin deficiency results in secondary deficiency or mislocalization of virtually every component of the DAPC. Ultimately, it will be critical to distinguish which aspects of DMD are caused by these secondary deficiencies. By considering the various domains of the dystrophin protein, specific biochemical deficits and physiological perturbations associated with deletions of those regions and the effects of restoring regions of the protein in transgenic mdx mice, it is possible to begin to develop a functional biology of dystrophin that may reveal multiple therapeutic targets.
