Spotlight on Research 2012

June 2012

DUX4-Regulated Genes Provide a Roadmap for Facioscapulohumeral Dystrophy Therapies

Analysis of the hundreds of genes regulated by the DUX4 transcription factor reveals a new understanding of the pathology of facioscapulohumeral dystrophy (FSHD) and may lead to tools that accelerate the development of therapies, according to a new study supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases. The study’s authors, from the Fred Hutchinson Cancer Research Center in Seattle and other institutions, believe that the results of their research might lead to novel treatment strategies for this inherited disease, which involves progressive weakness and wasting of face, shoulder and upper arm muscles. The work was reported in Developmental Cell.

Previously, Stephen J. Tapscott, M.D., Ph.D., and his colleagues showed that the DUX4 transcription factor is normally expressed in the cells that generate sperm in the male testes in all individuals, but that it is abnormally expressed in the skeletal muscle of people with FSHD. In the current study, they found that the mis-expression of the DUX4 factor in FSHD patients activates or inhibits many of the same genes in skeletal muscle. This dysregulation appears to damage the mature skeletal muscle tissue. In addition, the investigators discovered that DUX4 induces the expression of a gene called DEFB103 that inhibits muscle regeneration. According to Dr. Tapscott, DUX4 creates a "double whammy" by damaging muscle and, at the same time, producing a factor that blocks the normal ability of muscle to regenerate.

In addition to revealing the molecular mechanisms that might cause FSHD, the current study identifies important candidate biomarkers of the disease that may be useful in clinical studies to monitor the rate of disease progression or, hopefully, the conversion of diseased muscle to healthy muscle. Because many of the DUX4-regulated genes are not expressed in normal muscle tissue, their level of expression in FSHD muscle can be used as a way to measure disease activity. The recently published study assessed expression of these candidate biomarker genes in biopsies of skeletal muscle, but also noted that some of these biomarkers might be identified in the blood of FSHD patients, which would be a great advance in monitoring patients’ response to future therapeutic trials.

"Discovering how a specific mutation causes a specific disease improves diagnosis and provides a rational basis for future therapies. I hope that our work on FSHD will provide a roadmap for drug discovery that attracts the interest of the major pharmaceutical companies," says Dr. Tapscott.

FSHD, one of the most common forms of muscular dystrophy, usually begins in the teenage years and progresses slowly. There is no treatment that can stop or reverse any form of muscular dystrophy, and therapies that can slow progression or prevent complications are very limited.

Support for this study was also provided by the National Institute of Neurological Disorders and Stroke, another National Institutes of Health component; Friends of FSH Research; the University of Washington Genome Sciences; and the University of Washington Child Health Research Center.

The mission of the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), a part of the U.S. Department of Health and Human Services’ National Institutes of Health (NIH), is to support research into the causes, treatment, and prevention of arthritis and musculoskeletal and skin diseases; the training of basic and clinical scientists to carry out this research; and the dissemination of information on research progress in these diseases. For more information about the NIAMS, call the information clearinghouse at (301) 495-4484 or (877) 22-NIAMS (free call) or visit the NIAMS website at http://www.niams.nih.gov.

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Geng LN, et al. DUX4 activates germline genes, retroelements, and immune mediators: implications for facioscapulohumeral dystrophy. Dev Cell. 2012 January17; 22(1):38-51. Epub 2011 Dec 29. PMID: 22209328.