DISSECTING THE MOLECULAR MECHANISM OF FACIOSCAPULOHUMERAL MUSCULAR DYSTROPHY

People with FSHD typically have abnormally short strings of repeated DNA sequences, called D4Z4, on chromosome 4. We studied human muscle tissues from normal individuals and from people with FSHD. We analyzed the expression of genes located near the D4Z4 region and found that activity of three genes, ANT1, FRG1, FRG2, was elevated in the muscle from FSHD patients compared to that of other people. We also found that D4Z4 was necessary to bind a protein complex that normally suppresses gene activity. We hypothesized that deletions of copies of D4Z4 to a critical number reduce the number of these bound protein complexes, which in turn reduce control of nearby genes leading to disease. To verify our hypothesis we generated transgenic mice in which each one of the three genes, ANT1, FRG1, FRG2, is overactive. Interestingly, one of these genes, FRG1, causes muscular dystrophy when it is too active. This observation suggests that FRG1 can be responsible for the symptoms of FSHD. To fully understand FSHD pathogenesis, we aim: 1. To elucidate the mechanism underlying the control of gene transcription at 4q35. 2. To investigate the role of 4q35 gene over-expression in animal models. In summary, we expect functional analysis of genes in the FSHD chromosomal region and studies on mechanisms controlling gene expression to provide relevant information to understand the molecular basis of FSHD and to develop effective therapeutic strategies.