UMMS Scientists DISCOVER Genetic Key to Muscular Dystrophy

Newly identified genetic disorder appears to underlie cause

August 9, 2002

WORCESTER, Mass.—Researchers at the University of Massachusetts Medical School (UMMS) report today on a newly identified genetic cause that underlies a common neuromuscular disorder called facioscapulohumeral muscular dystrophy (FSHD), the third most common of the muscular dystrophies.  In the new study, Rossella G. Tupler, MD, PhD, and colleagues of the UMMS Programs in Gene Function & Expression and Molecular Medicine show that a genetic defect called “deletion” of certain repetitive DNA sequences in people with FSHD 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 (“Inappropriate gene activation in FSHD: A repressor complex binds a chromosomal repeat deleted in dystrophic muscle,”  Cell, Vol. 110, No. X, August 9, 2002, pp. 1 – 10.) 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 appear to play a role in the disorder.  This type of genetic problem—a deletion causing repetitive expression—has never before been identified in a human disease. 

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 a 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 less) have severe disease symptoms that begin in childhood; 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 weakness that primarily affects the face, shoulder blades and upper arms, although other muscles also deteriorate.   Despite intensive efforts, researchers have previously been unable to identify any genes that are altered in this disorder.

In this study, Dr. Tupler, and colleagues at UMMS and the Universita degli Studi di Pavia in Pavia, Italy, studied human muscle tissue from normal individuals and from people with FSHD as well as several other types of muscular dystrophy.  They then 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 and found that one part of the sequence was necessary to bind a protein complex that normally suppresses gene activity.  Deletions of copies of D4Z4 to a critical number reduced the number of these bound protein complexes, which in turn reduced control of genes from nearby parts of the chromosome.

"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 its activity with drugs or other treatments. “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,” says Tupler.

While most people with FSHD have D4Z4 deletions, about 5 to 10 percent of them do not.  These people may have mutations that affect the protein complex, Dr. Tupler says.  If researchers can confirm this, it would provide further information about this complex that is central to the development of this disorder, she notes.  Researchers have also identified people without FSHD who are missing the entire D4Z4 region and some 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 be linked to other human disorders.  For example there are DNA polymorphisms (usually considered normal variation of DNA repetitive sequences) near the insulin gene in Type 1 diabetes that 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.

The University of Massachusetts Medical School, one of the fastest growing academic health centers in the country, has built a reputation as a world-class research institution, consistently producing noteworthy advances in clinical and basic research.  The Medical School attracts more than $131 million in research funding annually, 80 percent of which comes from federal funding sources.  Research funding enables UMMS scientists to explore human disease from the molecular level to large-scale clinical trials.  Basic and clinical research leads to new approaches for diagnosis, treatment and prevention of disease. 


Mark L. Shelton, 508-856-2000

Related Links:
National Institute of Neurological Disorders and Stroke  web jump icon
Muscular Dystrophy Association
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CELL web jump icon