Facioscapulohumeral muscular dystrophy (FSHD) is one of the most common hereditary myopathies, with an incidence of 1 in 20,000. Insidious onset and progressive course characterize it. The disease has been causally related to deletion of tandemly arrayed 3.3 kb repeat units (D4Z4) on chromosome 4q35 possibly affecting chromatin organization and nearby gene expression. Consistently, we have observed that a number of genes mapping at 4q35 are over-expressed in the FSHD affected muscle. We have also discovered that within D4Z4 unit a 27 bp DNA element has a protein-binding activity. Through biochemical purification, we have isolated three proteins, YYI, HMGB2, and nucleolin, forming a multi-protein complex that binds D4Z4. We have been also able to demonstrate that this multi-protein complex is involved in silencing of gene located at 4q35. Our data suggest that D4Z4 elements contribute to 4q35 gene silencing through the interaction with a transcriptional repressing complex. We propose that the reduction of D4Z4 tandemly repeated units to a critical threshold might induce the over-expression of 4q35 genes and, as a consequence, trigger FSHD pathogenesis. In this proposal we present an experimental plan to dissect the FSHD pathogenic process through the analysis of the molecular events occurring at D4Z4.
Our aims are: 1. To elucidate the mechanism underlying the control of gene transcription at 4q35. 2. To identify 4q35 genes specifically involved in FSHD pathogenesis. 3. To investigate the role of 4q35 gene over-expression in animal models. In summary our studies on mechanisms controlling gene expression in the FSHD chromosomal region and characterization of 4q35 genes and will provide relevant information to understand the molecular basis of FSHD and to develop effective therapeutic strategies.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
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Special Emphasis Panel (ZRG1-SMB (01))
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Porter, John D
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University of Massachusetts Medical School Worcester
Schools of Medicine
United States
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