DISSECTING THE MOLECULAR MECHANISM RESPONSIBLE FOR FACIOSCAPULOHUMERAL MUSCULAR DYSTROPHY

FSHD is one of the three major muscular dystrophies. It is transmitted as an autosomal dominant trait. The FSHD genetic locus has been mapped in the very distal part of chromosome 4 long arm and chromosomal rearrangements were revealed in familial and sporadic FSHD cases. Those rearrangements correspond to deletions of repeated units occurring in the 4q subtelomeric heterochromatin (D4Z4). It has been postulated that heterochromatic elements within the repeat are essential for maintaining or establishing proper chromatin structure of this region. D4Z4 deletions might cause rearrangements of chromatin structure affecting gene expression in the vicinity. Chromatin condensation is a known control mechanism of gene expression. In FSHD genes located in 4q35 might be switched on and off depending on either the distance from D4Z4 or the length of the deleted repeat. Chromatin functional organization is established by the interaction between definite DNA sequences and protein complexes. Therefore, aimed at determining if there is any nuclear factor binding a definite sequence within D4Z4, we studied the interaction between D4Z4 DNA elements and nuclear proteins. We isolated a protein known to partecipate to chromatin architecture. For the first time we have been able to provide experimental evidences of the functional role of D4Z4. Thus our further experiments will dissect the molecular events occurring at 4q35 leading to FSHD onset. In conclusion our observation represents a starting point to investigate the role of D4Z4 in determining the 4qter chromatin structure. We believe that these findings are a crucial point for the delineation of the molecular basis of FSHD pathogenesis. Our project represents a new strategy towards the identification of the molecular defects that are critical for the FSHD pathogenesis. The results of this study will provide the basis to develop an appropriate therapy for FHSD.