Not One But Two DNA Changes Are Needed to Cause FSHD

Facioscapulohumeral muscular dystrophy (FSHD) requires the presence of not one but two genetic changes, both on chromosome 4, before it causes its characteristic symptoms — weakness starting in the muscles of the face, shoulder blade area and upper arms, with possible progression to other parts of the body.

The new findings, announced online Aug. 19, 2010, in the journal Science, have immediate implications for diagnosis and prediction of FSHD, and possible long-term implications for its treatment.

"Our study puts forward a plausible, genetic model for FSHD," the paper's authors say. They note that their study "not only explains the striking chromosome specificity of the disorder, but also provides a genetic mechanism that may unify the genetic observations in patients with FSHD."

About the new findings

A multinational team of scientists and physicians from the Netherlands, the United States, France and Spain collaborated on the project, which involved a combination of clinical and scientific research.

MDA grantee Silvère van der Maarel, at Leiden (Netherlands) University Medical Center, coordinated the study team, which included Rabi Tawil, who co-directs MDA's neuromuscular disease clinic at the University of Rochester (N.Y.) Medical Center, and former MDA grantee Stephen Tapscott at the Fred Hutchinson Cancer Research Center in Seattle. Van der Maarel, Tawil and Tapscott are part of the Fields Center for FSHD and Neuromuscular Research, a "center without walls" that represents a collaborative relationship among scientists at the University of Rochester and Leiden University Medical Center, as well as Stephen Tapscott.

The investigators found that two genetic requirements, located near each other on the tip of chromosome 4, must be combined for FSHD symptoms to appear. One requirement is a deletion of some of the DNA in a region of chromosome 4 called D4Z4. The second is a particular variant of DNA further toward the tip of chromosome 4 than the D4Z4 region.

The variant contains a "polyadenylation" signal which stabilizes otherwise fragile genetic instructions, called RNA transcripts, after they're synthesized from DNA (genes).

The presence of a polyadenylation signal makes it more likely that genetic instructions will stick around long enough to be translated into proteins (the final product of DNA and RNA instructions). In this case, the signal appears to make it possible for one or more potentially toxic proteins to be produced.

Background on the new findings

The involvement of the D4Z4 region of chromosome 4 and the fact that part of it is missing in FSHD have been known to scientists since the mid-1990s.

But just how a contracted D4Z4 region causes this muscle disease has been the subject of much debate over many years (see Through the Looking Glass with FSHD Researchers). The mystery deepened recently when it became clear that not everyone with a contracted D4Z4 region develops FSHD.

First, the researchers confirmed findings announced last year by an MDA-supported group coordinated by Tapscott that also included van der Maarel and Tawil.

Those findings showed that, in people with FSHD, the D4Z4 DNA region is active, meaning DNA is transcribed into RNA, which can then be used to make protein molecules. Normally, the D4Z4 region is silent. They paid particular attention to a gene called DUX4 (see Abnormal Activation), which they found could interfere with normal muscle development in laboratory experiments.

In the new investigation, more than 300 people with FSHD and more than 2,000 people without the disease were studied. All the people with FSHD had a contracted D4Z4 region on chromosome 4 and at least one of three "permissive" DNA sequences further out toward the tip of the same chromosome. The "permissive" sequences turned out to be polyadenylation signals.

Among the more than 2,000 people without any FSHD symptoms that the investigators studied, there were some who had contracted D4Z4 regions on chromosome 4. However, they all had "nonpermissive" signals further out on the chromosome. Without a polyadenylation signal, the researchers believe, RNA from the D4Z4 region doesn't last long enough to cause muscle-cell damage.

Meaning for people with FSHD

The new findings will make it easier to diagnose FSHD in someone with symptoms and predict who will develop the disease in someone without symptoms.

Now, the hunt is on for which proteins or genetic instructions (RNA) are causing the problem for muscle tissue in FSHD. Once DUX4, and possibly other proteins, are established as culprits, therapeutic strategies to block these proteins or their RNA could be developed.

Further laboratory studies will be needed before candidate therapies can be identified, after which they will need to be extensively tested in animals before being tried in humans with FSHD.

Read the MDA press release about this finding.

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