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Scientists identify a new kind of genetic problem in muscular dystrophy

NIH/National Institute of Neurological Disorders and Stroke

A newly identified genetic problem underlies a common neuromuscular disorder called facioscapulohumeral muscular dystrophy (FSHD), scientists say. In a new study, they show that deletion of repetitive DNA sequences in people with this disorder allows nearby genes to go into overdrive. The finding solves a decade-old riddle about the cause of this disorder and may ultimately lead to the first effective treatments.

The study found that abnormally short strings of repeated DNA sequences on chromosome 4 interfere with the function of a protein complex that controls nearby genes. This leads to over-activity of several genes that may play a role in the disorder. This type of genetic problem has never before been identified in a human disease. The study was funded in part by the National Institute of Neurological Disorders and Stroke (NINDS) and appears in the August 9, 2002, issue of Cell.*

Scientists first linked the short strings of DNA in this region to FSHD in 1992. People with FSHD typically have fewer than 11 copies of this nucleic acid sequence, called D4Z4, due to a deletion of part of the chromosome. In contrast, people without the disorder usually carry between 11 and 150 copies of the sequence. People with a very small number of copies (three or fewer) have severe disease symptoms that begin in childhood, while those with several more copies typically have milder symptoms that begin in the teens or early adulthood. However, until now, researchers have been unable to determine exactly how the number of DNA sequences influences the disease.

FSHD is the third most common inherited neuromuscular disorder, affecting one in every 20,000 people (only Duchenne muscular dystrophy and myotonic dystrophy are more common). People with FSHD have progressive muscle degeneration that primarily affects the face, shoulder blades, and upper arms, although other muscles also deteriorate. Despite intensive efforts, researchers have been unable to identify any genes that are altered in this disorder.

In the new study, Rossella Tupler, M.D., Ph.D., of the University of Massachusetts Medical School in Worcester and the Universita' degli Studi di Pavia in Pavia, Italy, and colleagues studied human muscle tissue from healthy individuals and from people with FSHD as well as several other types of muscular dystrophy. They analyzed the expression of three genes located near the D4Z4 region and found that activity of all three genes was elevated in the muscle from FSHD patients compared to that of other people.

The researchers also analyzed the interaction between the D4Z4 sequence and proteins present in the nucleus of the cell. They found that one part of the sequence binds to a protein complex that normally suppresses gene activity. Having fewer than 11 copies of D4Z4 reduced the number of functional protein complexes, which in turn reduced control of genes from nearby parts of the chromosome.

"This breakthrough is important scientifically, as it teaches us about novel ways genes can influence disease, which will someday help not only those people who suffer from FSHD, but hopefully, others as well," says Katrina Gwinn-Hardy, M.D., a program director at NINDS.

The researchers do not know which of the overactive chromosome 4 genes is responsible for the symptoms of FSHD. One of the genes they considered, called ANT1, triggers cell death when it is too active. Therefore it may be responsible for the progressive loss of muscle cells in this disorder. However, FSHD is a complex disease, and other genes or environmental factors also may play a role.

"These findings have specific implications for the disease, and general implications for genetic research," says Dr. Tupler. Knowing how the D4Z4 deletions affect nearby genes points to new strategies for treating the disorder. For example, researchers might be able to find a way to mimic the effect of the protein complex that goes awry in this disorder, thereby reducing the activity of all the affected genes. If a specific gene that causes the disorder can be identified, researchers also might be able to slow or halt that gene's activity with drugs or other treatments.

While most people with FSHD have D4Z4 deletions, about 5 to 10 percent do not. These people may have mutations that affect the protein complex, Dr. Tupler says. Researchers have also identified people without FSHD who are missing the entire D4Z4 region and several nearby genes. This suggests that an abnormal D4Z4 region somehow creates havoc in muscle cells and/or that the nearby genes are necessary for development of the disease.

The findings also suggest that repetitive DNA sequences play a previously unsuspected role in human disease by influencing gene activity, Dr. Tupler says. About 40 percent of the human genome is comprised of these repetitive sequences, and they might play a role in several other human disorders. For example, certain variations in repetitive DNA sequences near the insulin gene in Type 1 diabetes have been linked to insulin levels and birth size. Other DNA repeats have been associated with bladder cancer. Studies of sequences like these could lead to a much better understanding of how gene activity is regulated, Dr. Tupler suggests.

Scientists can now focus on identifying which genes on chromosome 4 contribute to FSHD and how to regulate the gene activity, says Dr. Tupler. "Hopefully, other researchers will help with that," she adds.


The NINDS is a component of the National Institutes of Health in Bethesda, Maryland, and is the nation's primary supporter of biomedical research on the brain and nervous system.

*Gabellini D, Green MR, Tupler R. "Inappropriate gene activation in FSHD: A repressor complex binds a chromosomal repeat deleted in dystrophic muscle." Cell, Vol. 110, No. 3, August 9, 2002, pp. 339-348.

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