Progress Update: FSHD Related Defects in Human Myogenesis

First Year Summary of FSHD research progress.

Gene expression profiling of cells from FSHD muscle biopsies suggests an intriguing hypothesis for the pathophysiological basis of FSHD: a primary defect in muscle cell differentiation. We proposed to test this hypothesis by comparing gene expression patterns in skin cells from FSHD patients before and after they are induced to form muscle. The identification of FSHD-linked cellular phenotypes would provide a focus for experimentation that may allow identification of molecular mechanisms of the disease process. In collaboration with Dr. Stephen Tapscott, we have identified gene expression profiles that appear to be unique to cells from FSHD patients. Now we can begin to focus on specific molecular pathways that are consistently altered in cells from individuals with FSHD, and attempt to identify gene regulatory elements that are common to the genes in a particular pathway.

A related but separate focus of our studies has been to identify transcribed sequences arising from the D4Z4 repeat unit and determine how disease-causing repeat array contractions result in changes in transcription. We have analyzed transcription from D4Z4 repeat sequences in a variety of cell types and identified gene regulatory elements responsible for initiating transcription of sequences encoding the Dux4 gene. We are now in a position to determine how chromosomal context and D4Z4 repeat array size influences transcription uniquely on one allele of chromosome 4 where array contractions result in FSHD.

See Grant: FSHD Related Defects in Human Myogenesis