MDA RESEARCHERS IDENTIFY RNA MECHANISM THAT CAN CAUSE MYOTONIC DYSTROPHY; OPEN NEW AREA OF INVESTIGATION FOR RANGE OF DISORDERS

TUCSON, Ariz., May 1, 1998 -- MDA-funded researchers at Baylor College of Medicine in Houston have uncovered a new mechanism for genetic disease. The discovery shows how a defect in RNA-based processing of genetic messages causes myotonic muscular dystrophy (MMD), the most common adult form of nine muscle-wasting diseases, known collectively as muscular dystrophy, which affect some 250,000 Americans.

It also may help scientists unravel the mysteries of other disorders including sporadic amyotrophic lateral sclerosis (ALS or Lou Gehrig's disease), in which distinct genetic mutations have not been found, as well as Friedreich's ataxia, spinal bulbar muscular atrophy, and Huntington's. Data indicates that processing of genetic messages in these diseases may also be defective, and a faulty RNA-based processing mechanism may contribute to the pathogenesis of these progressive disorders.

"This is a eureka moment for research seeking therapeutics for myotonic dystrophy, a puzzling disease that can affect many organs and often gets worse from one generation to the next," said Dr. R. Rodney Howell, Chairman, MDA Scientific Advisory Committee. "The researchers have found a protein that regulates RNA processing in muscle, uncovering an important mechanism that could have broad application in understanding the pathogenesis of disease."

Myotonic muscular dystrophy involves progressive muscle weakness and atrophy, as well as some degree of myotonia, an inability to relax muscles after use. The disorder can also affect many other tissues, including the heart, central nervous system, gastrointestinal tract, eyes (causing cataracts) and endocrine system. It affects about one in 8,500 people and is inherited in a dominant fashion, meaning only one abnormal gene from one parent is sufficient to cause symptoms.

MDA grantee Thomas Cooper, associate professor of pathology at Baylor, led the research team, which published its results in the May 1 issue of the journal Science.

Building on earlier findings about myotonic dystrophy genetics, including the identification in 1992 by MDA-funded researchers of a DNA defect that causes myotonic dystrophy, Cooper's team found that the defective gene associated with myotonic dystrophy controls a number of other genes.

When RNA copies of the genetic information from the defective gene containing too many of the chemical sequences known as CUG repeats accumulate, a specific protein (CUG-binding protein or CUG-BP) sticks to those copies and prevents CUG-BP from processing RNA of other genes. This binding of RNA fosters a pile up in the muscle cell nucleus, instead of allowing the proper genetic information to get out into the main part of the cell.

The team studied a gene for a protein known as cardiac troponin T, which is involved in contraction of heart muscle, and found that processing of this gene's RNA is abnormal in people with myotonic dystrophy. They found that its abnormal processing is probably the result of a malfunctioning CUG-BP.

"Myotonic dystrophy is the first human disease known to be caused by an accumulation of RNA," Cooper said. "This accumulation increases the processing of a fetal form of the cardiac troponin T gene, and may cause heart problems in many myotonic dystrophy patients by reducing production of the needed adult form of the cardiac troponin T protein. The essential CUG-BP is simply not available to assist in the expression of the proper gene. We also found many other genes that are likely to be regulated by CUG-BP and may express altered RNAs in myotonic dystrophy."

Cooper said his group's findings don't invalidate any other hypotheses about myotonic dystrophy. He said there are three hypotheses about the causes of myotonic dystrophy now being considered, and any or all of them may be true. Two have to do with direct effects on chromosome 19 genes. The third, proposed by Lubov Timchenko, co-author on this study and an MDA grantee, has to do with the effect of the chromosome 19 gene defect on CUG-BP, which in turn may affect many other genes. This could explain why so many tissues are affected in myotonic dystrophy, Cooper said, because when CUG-BP is not available to help with the expression of other genes' RNA, it could cause conditions often associated with myotonic dystrophy.

MDA is the nation's leading nongovernmental funder of research into neuromuscular diseases. By annually funding some 400 scientific teams worldwide, its investigators have made significant advances toward cures for several muscle-wasting disorders. They've also pioneered breakthroughs that may lead to therapies for heart disease, cancer, AIDS, Alzheimer's, Parkinson's, Huntington's, and cystic fibrosis.

MDA is the first voluntary health agency recognized by the American Medical Association with a Lifetime Achievement Award "for significant and lasting contributions to the health and welfare of humanity." The agency is working to defeat 40 neuromuscular diseases through programs of worldwide research, comprehensive patient and community services, and far-reaching public health education. For more information about MDA, and/or referrals to its clinics or its new ALS center, call 1-800-572-1717. Information about MDA is also available electronically through its Internet Web site (www.mda.org).

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