FSHD affects over 25,000 individuals in the United States. It is the third most common muscular dystrophy by incidence but may be the most common by prevalence (Orphanet, 2008). The DNA lesion causing this disease is a contraction within a series of 3.3 kb repeats (D4Z4 repeats) near the telomere of 4q. The contraction modifies the chromatin configuration of 4q35.2, which results in misexpression of a gene encoded within each D4Z4 repeat, DUX4. DUX4 is cytotoxic when overexpressed in various cellular model systems. However a pathological mechanism still eludes the field. We do not have a clear picture of which cell types in muscle express DUX4, nor when expression is initiated during development, nor how a transcriptionally active D4Z4 array affects development, muscle physiology, or regeneration. In addition, genetic correction of such a large deletion is not trivial. To address these questions, we have derived iPS cell lines from FSHD patients and controls. We propose a series of studies directed towards innovative approaches to genetic correction of this locus (Aim 1) and to developing a better understanding of myogenesis and the mechanism underlying the pathology in FSHD (Aim 2).
The mechanism of muscle degeneration in FSHD is engimatic. Unlike Duchenne's and other Dystroglycanopathies, FSHD neither presents evidence of ongoing muscle fiber damage, nor evidence of ongoing regeneration. The mutation that causes FSHD is known, but the way in which that mutation affects muscle physiology is not understood. We have generated iPS cells from FSHD patients. These are cells from the skin that have been reprogrammed into an earlier state, such that they can differentiate into any cell type in the petri dish. We propose to use newly-developed gene targeting technology to correct the FSHD mutation, and to study muscle development from the parental and the corrected iPS cells.