DUX4 Causes Muscle Mayhem in FSHD

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Editor's note 2/2/12: This story was updated to reflect the availability of a podcast in which Stephen Tapscott is interviewed.

A little over a year ago, a team of researchers announced a crucial new finding that helped explain the molecular basis of facioscapulohumeral muscular dystrophy (FSHD).

It was in October 2010 that Stephen Tapscott at the Fred Hutchinson Cancer Research Institute in Seattle, and colleagues, showed that abnormal production of a protein called DUX4 is a major molecular cause of FSHD. This research was supported in part by MDA.

The full-length form of DUX4 is normally found only in stem cells. When it's mistakenly produced in mature muscle fibers, it causes trouble, the researchers found. Until now, however, little has been known about the specific nature of the trouble caused by DUX4.

Full-length DUX4 affects other genes and proteins

Now, a multinational team coordinated by Tapscott has found that full-length DUX4 protein, produced in the wrong place (mature muscle fibers) and at the wrong time (much later than normal), affects the behavior of many other genes and proteins, with adverse consequences for muscle tissue.

Through complex interactions with genes that give rise to numerous proteins, inappropriate production of DUX4 in muscle tissue has several deleterious effects, the researchers say.

Among these are:

• suppressing muscle-cell differentiation, the process by which cells normally mature and take on specialized roles;

• causing the death of muscle cells by activating a cellular program called apoptosis;

• stimulating production of proteins the immune system may view as a threat and thereby inviting an immunologic attack on muscle tissue; and

• increasing production of myostatin and defensin, proteins that inhibit muscle growth and development.

Identifying DUX4's effects may lead to therapies, biomarkers

In their paper, published in the Jan. 17, 2012, issue of Developmental Cell, the researchers say their data "support the model that inappropriate expression of DUX4 plays a causal role in FSHD skeletal muscle pathophysiology" and that "one therapeutic avenue to pursue for FSHD is to reduce the activity of DUX4."

That's a strategy MDA is pursuing through, for example, current research grants to:

• Michael Kyba at the University of Minnesota to study inhibitors of DUX4;

• Eric Wagner at the University of Texas Health Science Center in Houston to investigate the role of DUX4 and test agents that inhibit its expression; and

• Fedik Rahimov at Harvard Medical School and Children's Hospital Boston to investigate the mechanisms by which DUX4 activity in FSHD-affected muscles leads to FSHD.

Tapscott and his colleagues also note that the altered levels of several proteins caused by the presence of full-length DUX4 may provide researchers with candidate biomarkers that they can follow to gauge the progression of FSHD or its response to experimental treatments.

Although MDA did not directly support this work, study team member Silvere van der Maarel has MDA funding for related work at Leiden University Medical Center in the Netherlands, and some of Tapscott's earlier work that led to this study received MDA support. Tapscott is a former member of MDA's Scientific Advisory Committee.

Podcast with Tapscott available

An interview with Stephen Tapscott is available as an 11½-minute podcast.

For more information

• International Research Team Discovers Genes and Disease Mechanisms Behind a Common Form of Muscular Dystrophy: a news release from the Fred Hutchinson Cancer Research Center, Jan. 12, 2012

• DUX4 Activates Germline Genes, Retroelements and Immune Mediators: Implications for Facioscapulohumeral Dystrophy: a summary of the scientific paper published Jan. 17, 2012, in Developmental Cell

• Early-Life Protein, Made Too Late, Causes Trouble in FSHD: A protein called DUX4, normally active only during early development, probably damages FSHD-affected muscle fibers and could become a target for drug development, Quest News Online, Oct. 29, 2010

• Not One But Two DNA Changes Are Needed to Cause FSHD: Two DNA changes on chromosome 4 — a contracted DNA segment and a "permissive" DNA signal — are needed to cause FSHD, Quest News Online, Aug. 19, 2010

• FSHD: Abnormal Activation: New findings show abnormally activated parts of a gene called DUX4 may underlie FSH dystrophy, Quest News Online, Aug. 27, 2009