MDA Scientists Find New Disease Mechanism Causes Common Dystrophy
TUCSON, Ariz., Aug. 9, 2002 — Scientists funded by the Muscular Dystrophy Association have shown that a unique defect in gene regulation, never before seen in human disease, causes one of the most common forms of muscular dystrophy. The finding offers hope for people with the disease, and might hold clues to the causes of other puzzling diseases, including insulin-dependent diabetes and bladder cancer.
For some 14,000 Americans, facioscapulohumeral muscular dystrophy (FSHD) causes progressive wasting of muscles in the face, shoulders and upper arms, making it difficult to walk, lift the arms or even smile.
For years, the genetic defect underlying FSHD eluded scientists, but the MDA-funded team has identified a complex causal mechanism: In the Aug. 9 issue of Cell, they report that FSHD occurs because an absent piece of DNA allows nearby genes to become overactive.
By 1992, the cause of FSHD had been traced to a deletion in a region of chromosome 4 called D4Z4, which is made up of repeating units of DNA.
At that time, many scientists assumed that FSHD would fit the mold for other genetic diseases, and they'd find one or a few defective genes within D4Z4. But exhaustive searches turned up nothing.
The new study, led by Italian scientist Rossella Tupler, shows that D4Z4 actually represses the activity of genes nearby. When it's incomplete, as in FSHD, those genes are inappropriately switched on and run amok.
"The mechanism we describe is entirely new and represents an intriguing model for approaching other complex disorders in which the candidate gene approach was not successful," said Tupler, who holds appointments at the Università degli Studi di Pavia in Italy and the University of Massachusetts Medical School in Worcester.
By examining muscle biopsies, Tupler and her colleagues, Davide Gabellini and Michael R. Green, found that, in FSHD, at least three genes close to D4Z4 are more active than normal.
They also identified a piece of D4Z4 that acts as a docking site for transcriptional repressors – proteins that attach to DNA and turn off genes. Finally, they showed that by experimentally blocking the repressors in non-FSHD cells, they could reproduce the abnormal gene activity seen in FSHD.
It's not clear how the uncontrolled activity of genes near D4Z4 leads to FSHD, Tupler notes, but added that "it might be possible to design therapies that control the [overactive] genes."
There's a good chance that this type of gene misregulation is responsible for other diseases, she said, noting that repeating units of DNA, some similar to D4Z4, make up about 40 percent of the human genome (the complete set of human genes). For example, DNA regions similar to D4Z4 are located in the insulin gene and near a gene linked to bladder cancer.
MDA Director of Research Development Sharon Hesterlee said, "This study is a good example of the way MDA-supported research gives us a better understanding not only of the muscular dystrophies, but also of disease biology in general."
MDA is the nonprofit health agency dedicated to curing muscular dystrophy, ALS and related diseases by funding worldwide research. The Association also provides comprehensive health care and support services, advocacy and education. For more information about MDA's programs, call (800) 572-1717 or go to www.mda.org.
