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 t
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Contact: Natalie Frazin or Paul Girolami
301-496-5751
NIH/National Institute of Neurological Disorders and Stroke
8-Aug-2002