FSHD muscular dystrophy: molecular pathogenesis and prospects for therapy

The goal of this research project is to understand the molecular mechanism of facioscapulohumeral muscular dystrophy (FSHD). FSHD is the third most common muscular dystrophy. Presently, there is no treatment or cure for FSHD. FSHD is associated with reduction in the number of copies of DNA on chromosome 4, called D4Z4, that is repeated may times toward the end of the long arm of chromosome 4. We have found that D4Z4 controls the activity of nearby FSHD genes. We have found that in FSHD patients there is an increased production of the proteins encoded by the genes close to D4Z4. Interestingly, we have found that these proteins are over-produced specifically in the muscles of FSHD patients explaining the fact that FSHD is primarily a disease of skeletal muscle. More recently, with the idea of modeling in an animal the same conditions observed in FSHD patients, we generated mice over-producing the same proteins that are over-produced in the muscles of FSHD patients. We have found that mice over-producing a protein called FRG1 display several features of FSHD patients. Based on these results, we propose that loss of D4Z4 causes over-production of FRG1, which leads to FSHD. We plan to: - understand the molecular mechanism responsible for increased production of 4q35 proteins in FSHD - understand the specific processes that go awry in muscles of patients suffering from FSHD - test possible therapeutic treatments. Results of our research will contribute to develop effective therapeutic approaches for FSHD.