Discovery opens door to therapeutic development for FSH muscular dystrophy

Scientists are closer to understanding what triggers muscle damage in one of the most common forms of muscular dystrophy, called facioscapulohumeral muscular dystrophy (FSHD). FSHD affects about 1 in 20,000 people, and is named for progressive weakness and wasting of muscles in the face, shoulders and upper arms. Although not life-threatening, the disease is disabling. The facial weakness in FSHD, for example, often leads to problems with chewing and speaking.

The new research was funded in part by the National Institutes of Health and appears in the journal Science. Until now, there were few clues to the mechanism of FSHD and essentially no leads for potential therapies, beyond symptomatic treatments, said John Porter, Ph.D., a program director at NIH's National Institute of Neurological Disorders and Stroke (NINDS).

"This study presents a model of the disease that ties together many complex findings, and will allow researchers to test new theories and potential new treatments," Dr. Porter said.

In the early 1990s, researchers found that FSHD is associated with a shortened DNA sequence located on chromosome 4. Experts predicted that discovery of one or more FSHD genes was imminent, but while a handful of candidate genes gradually emerged, none of them were found to have a key role in the disease.

The mysteries surrounding FSHD deepened in 2002 when researchers, led by Silvere van der Maarel, Ph.D., at Leiden University in the Netherlands, found that the shortened DNA sequence on chromosome 4 is not enough to cause FSHD. They discovered that the disease occurs only among people who have the shortened DNA sequence plus other sequence variations on chromosome 4. That work was funded in part by NIH, the FSH Society and the Muscular Dystrophy Association.

The new study proposes a model that explains how the previous findings fit together. The study was led by Dr. van der Maarel in collaboration with Stephen Tapscott, M.D., Ph.D., at the Fred Hutchinson Cancer Research Center in Seattle, and Rabi Tawil, M.D., at the University of Rochester Medical Center in New York.

At one end of chromosome 4 is a chunk of repetitive DNA, called a tandem repeat array. Normally this region contains 10-100 repeating units of DNA, but in most people with FSHD, the array is smaller, with fewer than 10 repeats. Within each repeating unit is a gene called DUX4.

The researchers found that in people with FSHD, the DUX4 gene generates a piece of RNA that is toxic to muscle cells. RNA is a sister molecule to DNA with many critical functions. The researchers also discovered that variations on chromosome 4 are important because they affect the durability of DUX4 RNA. People with FSHD have chromosome variations that add a trailing segment to the RNA called a poly(A) tail. With the poly(A) tail attached, the RNA is more stable and more likely to cause damage.

The researchers came to these conclusions by creating artificial DNA constructs containing the short repeat array, in combination with different variations on chromosome 4. They inserted these constructs into muscle cells, and analyzed how the chromosome 4 variations affected the level of DUX4 RNA. They also studied FSHD families with unique chromosome rearrangements and showed that all families with FSHD shared chromosome 4 sequences encoding the poly(A) tail.

In another set of experiments, they found they could detect DUX4 RNA in muscle cells from individuals with FSHD but not in cells from unaffected individuals. Meanwhile, previous studies have shown that DUX4 can trigger muscle cell death.

"This study provides evidence that DUX4 RNA is likely a key part of the disease process in FSH muscular dystrophy, and justifies further investigation of its role and how to silence its effects," Dr. Tapscott said.

Source: NIH/National Institute of Neurological Disorders and Stroke