PATHOPHYSIOLOGY OF FACIOSCAPULOHUMERAL MUSCULAR DYSTROPHY (FSHD): TRANSCRIPTION FROM THE 4q35 LOCUS, GENE EXPRESSION PROFILING AND PROTEOME ANALYSIS IN MUSCLES DERIVED FROM NORMAL AND FSHD PATIENTS

The identification of the 4q35 molecular defect in patients affected by facioscapulohumeral muscular dystrophy (FSHD) and the availability of a simple diagnostic test for the disease greatly improved the reliability of molecular diagnosis. However, the high degree of phenotypic variability also in individuals belonging to the same family and carrying identical EcoRI fragments and the presence of nonpenetrant gene carriers, represent a limitation to the diagnostic and prognostic value of this molecular parameter. Therefore, additional markers are needed that can cope with the phenotypic complexity of the disease. Recently the human genome project has been completed and new sophisticated techniques are emerging as powerful tools to approach the complexity of human diseases. Genome wide application of expression profiling study has already shown to be a valid tool in many human diseases. Allowing clinical and molecular research to merge in feasible projects they promise to open a new era in the research on genetic disorders and muscular dystrophies. Since we believe that this approach should be extensively pursued, we elaborated this project with the aim A) to search for RNAs transcribed from the D4Z4 repeat region and involved in coordination and modulation of genes differentially expressed in muscle from normal and FSHD individuals; B) to study the changes in gene expression profiling and proteome composition associated with the disease. We expect that the collaboration between clinicians and basic scientists with strong expertise in molecular genetics , microarray technology and proteome analysis of human skeletal muscle will provide new clues to FSHD pathogenesis. These will turn out useful in diagnosis, in clinical prognosis and genetic counseling of the disease. In addition the results of this study will identify molecular markers and specific targets for drug therapy.