The functional diversity of dystrophin

grantor: University of TorontoThe Duchenne muscular dystrophy (DMD) gene is complex, encoding multiple tissue specific isoforms of unknown function. The hypothesis that dystrophin isoforms are functionally distinct, and perform specialized roles in the tissues in which they are expressed is tested. Specifically, the role of Dp71, a small isoform of dystrophin that is expressed in many tissues, is examined to determine how its function is distinct from that of the full length isoform, Dp427. In Chapter II, it is demonstrated that there are a series of isoforms of Dp71 in most tissues that arise from inclusion or exclusion of exons 71. and 78. The changes introduced through alternative splicing of these exons may modulate protein interactions and hence the function of Dp71 in different tissues. It is demonstrated that Dp71 is expressed in the early stages of muscle development, the primary tissue affected in DMD. In primary myogenic cells, Dp71 has a cellular localization distinct from Dp427 supporting a distinct cellular role (Chapter III). It is hypothesized that this difference in localization may be due to protein binding site to Dp71 via a distinct binding motif not present in Dp427. In Chapter IV, an actin binding site within the unique N-terminus of Dp71 is shown to be sufficient for localization to stress fibres. In Chapter V, the distribution of dystrophin isoforms in the retina was examined. Dp427 and Dp260 are expressed at the outer plexiform layer of the retina, whereas Dp71 is localized to the inner limiting membrane of the retina. The non-overlapping expression pattern in the retina, suggests that both Dp71 and Dp260 are required for proper signal transduction through the neural retina.Ph.D