AN ANIMAL MODEL TO DEVELOP THERAPEUTIC STRATEGIES FOR FSHD

The goal of this research project is to understand the molecular mechanism of facioscapulohumeral muscular dystrophy (FSHD) and to develop effective therapeutic approaches. FSHD is the third most common form of muscular dystrophy. Its major symptom is the progressive weakening and loss of specific skeletal muscles. Presently, there is no treatment or cure for FSHD. Nearly all cases of FSHD are associated with a missing piece of DNA on chromosome 4. This piece of DNA is called D4Z4 and is repeated may times toward the end of the long arm of chromosome 4. We hypothesized that D4Z4 may control the activity of nearby FSHD genes. We found that in FSHD patients there is an increased production of the proteins encoded by the genes close to D4Z4. Interestingly, we 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. To understand the function of D4Z4 we studied its interaction with nuclear proteins. We found a multi-protein complex that bind a specific piece of D4Z4 and in normal conditions shuts-off the production of the proteins encoded by the genes close to D4Z4. 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 found that mice over-producing a protein called FRG1 display a variety of features found in FSHD providing the first animal model of the disease. Based on these results, we propose that loss of D4Z4 causes over-production of FRG1, which leads to FSHD. Currently, we are studying our mouse model to have a better understanding of the specific processes that go awry in the muscles of patients suffering from FSHD and to test possible therapeutic approaches.