Principal Investigators:

Dr. Brian Kennedy (University of Washington)
Dr. Stephen Hauschka (University of Washington)

The genetic event leading to Facioscapulohumeral muscular dystrophy (FSHD) has been identified in a majority of affected patients. Unlike other neuromuscular diseases, however, the mutation linked to FSHD does not alter a known coding region of a gene. Rather, affected individuals have a reduced number of D4Z4 DNA repeats on the distal tip of chromosome 4q (4q35). These repeats are thought to be important for the establishment of heterochromatic regions of DNA. A majority of evidence suggests that FSHD might arise due to an insufficient number of D4Z4 repeats. A protein complex containing YY1, HMGB2 and nucleolin has been identified that mediates transcriptional repression at genes in the vicinity of D4Z4 repeats including FRG1, FRG2 and ANT1, and data from some, but not all, investigators suggest these genes are overexpressed in muscle from FSHD patients. Interestingly, the 4q35 region localizes to the nuclear periphery and this localization is disrupted in cells lacking A-type lamins. Mutations in A-type lamins give rise to two forms of muscular dystrophy that have overlapping phenotypes with FSHD. We have generated myoblasts from mice lacking A-type lamins and shown that these cells have severe differentiation defects. From these experiments, we speculate that individuals with mutations in A-type lamins acquire dystrophic syndromes due to a lack of regeneration potential in adult muscle stem cells. Here, we propose experiments with two primary goals in mind. First, we will determine whether A-type lamin function is required for the establishment of heterochromatin at D4Z4 repeats, and examine the potential links between A-type lamin-associated muscle diseases and FSHD. Second, we will generate myoblast cell lines overexpressing genes normally localized near D4Z4 repeats and determine effects on the kinetics of muscle differentiation. Parallel studies will test an FSHD therapeutic strategy by reducing FRG1, FRG2 or ANT1 expression using siRNA. These studies will enhance our understanding of muscular dystrophies linked to abnormal nuclear structure and gene expression, and potentially identify candidate genes for future therapeutic approaches.