Update (Nov. 14, 2012): This story has been updated to reflect information about genetic testing.
Scientists funded in part by MDA have found the cause of type 2facioscapulohumeral muscular dystrophy (FSHD), a discovery that increases scientific understanding of both forms of FSHD, will improve diagnosis of the disease and could lead to treatment advances.
In the few years since accurate genetic testing for FSHD has been possible, it's been known that a small subset (about 5 percent) of people with FSHD symptoms don’t have a genetic hallmark of the disease: an abnormally shortened DNA sequence on chromosome 4. These patients were said to have type 2 FSHD (FSHD2), although how they developed FSHD symptoms remained unclear. Now, researchers have found that FSHD2 is linked to mutations in a gene known as SMCHD1.
Although SMCHD1 mutations are specific for FSHD2, the researchers found that there are important commonalities in the underlying processes in both FSHD1 and FSHD2.
MDA grantee Silvère van der Maarel at Leiden University in the Netherlands co-led a multinational group of researchers which found that SMCHD1 mutations, in combination with a second specific DNA sequence, can cause FSHD.
MDA grantee Silvère van der Maarel, professor of medical epigenetics at Leiden University in the Netherlands, with a multinational team of investigators, published these landmark findings online Nov. 11, 2012, in Nature Genetics.
Van der Maarel said the new findings could open "new roads to therapy."
By identifying mutations in the SMCHD1 gene as contributing to FSHD, the scientists say they've confirmed that a phenomenon known as chromatin relaxation is a major cause of both FSHD1 and FSHD2. They also note that the phenomenon may underlie other genetic conditions as well.
Chromosomes are made of chromatin, which consists of DNA and proteins wound into loose or tight structures. Loosely wound — also known as "open" or "relaxed"— chromatin permits cells to use DNA to manufacture proteins. Tightly wound — or "closed"— chromatin does not permit cells to use DNA to make proteins. Alterations in chromatin structure can lead to either activation or deactivation of protein production.
An underlying cause of both forms of FSHD is the inappropriate production of a protein called DUX4 in mature muscle fibers. Normally, the protein is not produced in significant amounts in muscle fibers, where it is toxic.
In FSHD1, which affects the vast majority of people with the disease, inappropriate DUX4 production in muscles results from a shortened stretch of DNA on chromosome 4, called the D4Z4 region, along with a particular "permissive" sequence of DNA at the tip of the same chromosome.
The shortened DNA section somehow leads to chromatin relaxation in the region, allowing the DUX4 gene to be turned on. The permissive sequence at the end of the chromosome stabilizes the newly made genetic instructions for DUX4.
When researchers found people with symptoms of FSHD who didn't have the abnormally shortened DNA sequence on chromosome 4, they used the term "FSHD2" as a general diagnosis. Now this diagnosis has a more specific meaning.
The new findings show that in FSHD2, a different genetic change can lead to chromatin relaxation. Van der Maarel and his colleagues have discovered that mutations in the SMCHD1 gene on chromosome 18, combined with the permissive DNA sequence on chromosome 4, likewise lead to toxic DUX4 production in muscle tissue.
The researchers found that in people with FSHD2, SMCHD1 mutations lead to insufficient amounts of the SMCHD1 protein, which is known to affect chromatin structure. SMCHD1 deficiency, the researchers have found, causes relaxation of the chromatin in the D4Z4 region of chromosome 4, even though the region is of normal length.
The researchers identified an SMCHD1 mutation in 15 out of 19 families who had FSHD symptoms but did not have the usual short region of DNA on chromosome 4 that characterizes FSHD1. Several different mutations in SMCHD1 were identified.
The researchers suspect that those families who did not have SMCHD1 mutations have other, as-yet-undiscovered mutations that predispose them to FSHD.
"The disease mechanisms of FSHD1 and FSHD2 converge at the level of D4Z4 chromatin relaxation and the… expression of DUX4," the study authors write.
They also say that it is likely that other causes of D4Z4 chromatin relaxation will be found that cause additional types of FSHD, and that SMCHD1 mutations may cause relaxation of chromatin in other parts of the genome, perhaps leading to other disorders.
The authors also say that SMCHD1 and proteins like it may act as modifiers of disease severity in FSHD1. (They might, for example, change the chromatin relaxation pattern.)
"With the identification of SMCHD1 in FSHD, we have identified the first FSHD-specific modifier of DUX4 expression," van der Maarel said. "This opens new roads to therapy, as we predict that, if we could increase SMCHD1 levels, this would be beneficial to patients. Current efforts are therefore not only focusing on offering a diagnostic service to a group of patients who could not be diagnosed molecularly, but also on ways to stabilize the SMCHD1 protein." (Genetic testing for FSHD1 is available in clinical laboratories around the world, but testing for FSHD2 is not available yet outside a research setting.)
In addition to van der Maarel, other key investigators on this study are Richard Lemmers of Leiden University, Daniel Miller at the University of Washington,Seattle, Stephen Tapscott at the Fred Hutchinson Cancer Research Center in Seattle and Rabi Tawil at the University of Rochester (N.Y.). Tapscott and Tawil are former MDA research grantees, and Tawil co-directs the MDA Clinic at the University of Rochester Medical Center.