'Turning Off the Switch' May Provide New FSHD Strategy

Researchers in Italy and Japan, supported in part by MDA, have identified what they believe is a molecular "switch" that may be inappropriately activating several genes in facioscapulohumeral muscular dystrophy (FSHD).

The finding provides the scientific community with a new target at which to aim experimental therapies for FSHD. Blocking the actions of this switch, dubbed DBE-T, could block the activation of multiple genes that are normally silent in mature muscle fibers, including the DUX4 gene that has been implicated in FSHD causation. DBE-T was found only in the cells of people with FSHD, not in normal cells.

MDA research grantee Davide Gabellini, at the San Raffaele Scientific Institute in Milan, Italy, coordinated the study team, which published its results online April 26, 2012, in the journal Cell.

New finding adds mechanism to existing knowledge

This new finding adds to a long and complex history of molecular research in FSHD that dates back to the early 1990s, when investigators first identified a region of DNA near the tip of chromosome 4 that appeared to contain an FSHD-causing mutation (genetic change).

Over the next decade or so, scientists determined that the mutation was unusual. It involved a deletion of some repeated DNA segments in a region of chromosome 4 called D4Z4. This region contains no actual genes, but it soon became clear that an intact D4Z4 region is necessary for neighboring genes to be properly activated (turned on) or inactivated (turned off).

By the early years of the 21st century, attention became focused on how the deletion in the D4Z4 DNA region affected nearby genes and on precisely which genes were affected.

Initial attention focused largely on a nearby gene called FRG1, which some researchers said was overactive — leading to overproduction of the FRG1 protein — in FSHD.

More recently, attention began to shift to a gene called DUX4, also located near the D4Z4 region on chromosome 4. It was discovered that DUX4, normally active only very early in life, is inappropriately activated in FSHD, causing disruption in muscle fibers.

The recent findings by Gabellini and colleagues do not refute the roles of either FRG1, DUX4 or other inappropriately activated genes in FSHD. However, they suggest a new mechanism by which the overactivation of these genes may occur and provide an "upstream" target at which to aim experimental therapies.

New model proposed for FSHD

Gabellini's group proposes a model for FSHD that goes like this:

1. The D4Z4 region is shorter than normal on a chromosome 4 bearing the FSHD mutation.
2. This shortening interferes with the silencing (also called deactivation or repression) of a stretch of DNA that leads to production of RNA. RNA is normally an intermediate step between DNA and protein synthesis, but sometimes (as in this case), there is no protein synthesis, and the RNA is called a noncoding RNA.
3. In FSHD (but not in normal cells), a noncoding RNA called DBE-T is produced. Like the DUX4 gene and possibly the FRG1 gene, the DNA for DBE-T is normally silenced (inactivated) in mature muscle fibers.
4. In FSHD-affected cells, DBE-T leads to the inappropriate activation of nearby genes in the region, such as DUX4 and FRG1.

DBE-T could be a new target in FSHD

Targeting DBE-T RNA to suppress its production or block its activities seems like a promising therapeutic lead for FSHD.

"Instead of targeting the inappropriate expression of individual genes, it could be more effective to target a general [chromosome 4] gene regulator," the researchers write in their April 26 paper. "It is tempting to speculate that DBE-T is a valid therapeutic target to achieve a general normalization of [chromosome 4] gene expression in FSHD."

MDA's development grant program played a role

Davide Gabellini’s first MDA award, given in 2003, was an MDA development grant, a type of award that’s given to new scientists who are making the transition from being a postdoctoral researcher in the laboratory of an independent scientist to becoming an independent scientist. The three-year grant allowed Gabellini to study the molecular basis of FSHD during a critical period early in his career.

In 2009, he received a three-year MDA research grant as an independent investigator to characterize the molecular mechanisms altered in FSHD.

Video online

Sanjay Bidichandani, MDA’s vice president of research, discusses the new FSHD findings in a five-minute video.