FSHD: Abnormal Activation

An MDA-supported team of scientists in the United States and the Netherlands has uncovered new leads about the origins of facioscapulohumeral muscular dystrophy (FSHD), a disease whose biochemical underpinnings have proved elusive to scientists despite years of investigation.

Lack of understanding of the mechanisms involved in FSHD has impeded treatment development, a phase of research that generally moves forward after disease mechanisms have been described.

About FSHD

FSHD is a form of muscular dystrophy that preferentially affects the muscles of the face ("facio"), shoulder ("scapulo") and upper arm ("humeral"). Affecting both males and females, it usually begins by age 20 and progresses slowly.

Difficulty smiling and upper-body weakness are typical of FSHD. The development of treatments has been hampered by lack of understanding of the disease process. This new research finding provides important clues to this process.

The genetic cause, a missing stretch of DNA (DNA "deletion") on chromosome 4, has been known since the 1990s. But attempts to pin down the specific effects of the DNA deletion, such as by finding specific genes in or near the region that have been altered by it, has led to more confusion than answers.

About the new findings

The new findings, published in the July issue of Human Molecular Genetics, focus on a gene known as DUX4, located near the end of chromosome 4 in the same region that harbors the FSHD-causing DNA deletion.

MDA supported work done by Sara Winokur at the University of California-Irvine, Silvere van der Maarel at Leiden University Medical Center in the Netherlands, and Galina Filippova at the Fred Hutchinson Cancer Research Center in Seattle. Rabi Tawil, who co-directs the MDA clinic at the University of Rochester (N.Y.) Medical Center, was also on the study team.

The researchers built on many previous studies, many of which have suggested that the loss of a DNA on chromosome 4 releases a molecular brake, activating genes in or near the deletion-containing region that would otherwise be inactive. Much of the focus until now has been on inappropriate activation of a chromosome-4 gene called FRG1.

DUX4 has been previously investigated as a culprit in FSHD, and some researchers found it to be active, whereas others have believed it to be inactive.

The new research supports both positions. DUX4 is for the most part inactive, it seems. However, it now appears that in FSHD-affected cells, pieces of DUX4 DNA are activated. They're transcribed into RNA (the first step a cell takes when making a protein molecule from an activated stretch of DNA) and some of these RNA pieces can then be translated into protein molecules.

One of the protein molecules made from the partially activated DUX4 gene was found to interfere with muscle development in cells in the laboratory. Other protein and RNA molecules from the abnormally activated DUX4 gene could have toxic effects as well, the researchers say. Therefore, any of them have the potential to become targets for therapeutic development.

Meaning for patients

There is no immediate potential for treatment from the new findings. However, if blocking or destroying one or more of the toxic pieces of RNA or protein improves or stabilizes weakness in an animal model of FSHD, a biotechnology company could become interested in developing the concept into a drug for human use. MDA supports this kind of drug development through its MDA Venture Philanthropy program (MVP).

If someone in your family has FSHD, you can help speed research by joining the National Registry of Myotonic Dystrophy & FSHD Patients and Family Members. This registry, supported by the National Institutes of Health and administered by the University of Rochester (N.Y.) Medical Center, connects patients with investigators.

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