BIOPHYSICAL AND BIOCHEMICAL STUDY OF NATIVE AND EDITED DYSTROPHIN ROD REGION

Duchenne Muscular Dystrophy (DMD) is a severe X-linked recessive disease affecting 1 in 3500 boys that is characterized by the degeneration of muscle function and strength. The cause of this disease lies in gene defects that eliminate expression of the protein dystrophin. Becker Muscular Dystrophy, BMD is a milder form of disease that has a later onset and much longer survival (up to the 7th decade of life, compared to median survival of 25 years for DMD patients) because of the presence of low levels of modified dystrophin protein. BMD is very heterogeneous, however, and many cases are nearly as severe as DMD. A major therapy for DMD involves exon skipping, which produces modified forms of dystrophin that are very similar to BMD. However, how these edits impact the function of dystrophin, and how they are linked to the severity of BMD or the BMD-like state produced in DMD exon skip therapy is unknown. We investigated this in two specific cases involving a specific panel of BMD defects linked to a major cause of death, dilated cardiomyopathy (DCM). We also investigated the contribution of various exons to interaction with a signaling partner of dystrophin, neuronal nitric oxide synthetase (nNOS).Ph.D. in Biological and Chemical Sciences, December 201