THURSDAY, Aug. 8, 2002 (HealthDayNews) -- Researchers have identified the genetic flaw that causes a common form of muscular dystrophy -- a missing segment of material that somehow makes a gene overproduce a destructive molecule usually kept under control.
"This is a big step forward for this particular disease," says Sharon Hesterlee, director of research and development for the Muscular Dystrophy Association. "There are two ways of looking for a therapy -- hit-or-miss or more rational. By understanding the causes of the disease, we can start designing therapies."
That work has already begun, says Dr. Rossella Tupler, who heads the group reporting the discovery in tomorrow's issue of the journal Cell.
"Now we are working with mice to try to see what we can do," she says. "If we can make a molecule that turns off the gene or suggest some behavior that will not make the gene overwork, it could lead to a therapy."
The condition is facioscapulohumeral muscular dystrophy (FSHD), a name that describes the part of the body affected by the disease -- the face, shoulder blades and arms, where muscles begin deteriorating in childhood or the teens.
FSHD, which affects about 20,000 Americans, is the third most common of the nine forms of muscular dystrophy, which collectively affect 300,000 people in this country. The two most common forms, Duchenne muscular dystrophy and myotonic dystrophy, each affect about 30,000 Americans.
The FSHD discovery is an important addition to the already large library of genetic information about the muscular dystrophies, Hesterlee says.
"There are 20 or 30 genes known to be involved in different forms of MD," she says. "This is the last holdout. We knew that people missing this little piece of DNA on chromosome 4 had the condition, but we did not know the particulars."
Tupler, an assistant professor of genetics at the Universita' degli Studi di Pavia in Italy who is currently at the University of Massachusetts Medical School, made the discovery by analyzing tissue from FSHD patients in Italy.
Since 1992, researchers have known that people with FSHD have abnormally short strings of repeated sequences of DNA, the genetic molecule, in a region designated as D4Z4 on chromosome 4, one of the 23 found in human cells. A normal cell carries as many as 150 D4Z4 repeats. In FSHD, there are no more than 11 -- and the fewer the number, the earlier and more severe the disease.
Tupler and her colleagues found the D4Z4 sequence binds to a protein complex that suppresses gene activity. A lack of that sequence means that a gene in its neighborhood goes into action when it should not. The specific gene has not been identified. One promising candidate is ANT1, a gene that can trigger cell death, but two other genes in the neighborhood are being investigated.
It is an unusual mode of action, Tupler says. "This mechanism has been described in some cells, but it has never been seen in animals or humans," she says.
It is also unusual for a muscular dystrophy, Hesterlee adds. In every other case, the condition is caused by a mutation of a gene. The genetics of a muscular dystrophy can be complex, she says. In one condition, limbgirdle muscular dystrophy (also named for the affected part of the body), 14 different mutations have been identified.
Slowly, that genetic information is being put to work.
"What we can offer parents and families is entry into trials where we are testing a number of approaches," Hesterlee says. "None of these is dramatic, but we do have long-term plans. We have one trial of gene therapy for limbgirdle muscular dystrophy."
What To Do
You can learn more about FSHD and other dystrophies from the Muscular Dystrophy Association or the National Institute of Neurological Disorders and Stroke.
