MDA RESEARCHES UNRAVEL
KEY MECHANISM IN COMPLEX DYSTROPHY

TUCSON, Ariz., Dec. 4, 2003 — A physician-investigator at Harvard Medical School and Beth Israel Deaconess Medical Center in Boston has uncovered a unique molecular mechanism that may help explain why myotonic muscular dystrophy, the most common form of muscular dystrophy in adults, is such a complex disease.

The work of Richard Junghans was funded by the Muscular Dystrophy Association.
The finding, which shows how several proteins can be affected by a single genetic flaw, is in today’s issue of Science Express, an online edition of the journal Science. Junghans was assisted by postdoctoral researcher Alexander Ebralidze and others.

“ This new understanding of myotonic dystrophy really demonstrates how far we’ve come from the old idea of ‘one gene, one protein, one disease,’ and as our understanding grows, so does our arsenal of treatment possibilities,” Junghans said.

Myotonic dystrophy, which affects some 38,000 people in the United States, causes muscle weakness, myotonia (difficulty relaxing muscles), premature balding, cataracts, digestive and gynecological abnormalities, heartbeat irregularities, and mild to moderate brain dysfunction. The disease varies in severity.

In 1992, MDA grantees were part of a multinational team that found that the underlying genetic defect in myotonic dystrophy is an abnormally large section of DNA on chromosome 19, which further expands as it’s passed from parent to child. In general, larger DNA expansions are correlated with earlier disease onset and more severe disease, so the disorder tends to worsen with each generation.

Junghans’ group has found that the mutated RNA in affected cells sticks to transcription factors, proteins the cell needs to make other proteins. The transcription factors allow the cell to read the genetic instructions in the DNA, convert these instructions to an RNA template, and then manufacture cellular proteins.

When the researchers added a transcription factor to the myotonic dystrophy-affected cells, the level of a specific protein they measured was restored to normal.

Junghans said that this is the first time that any abnormal RNA has been shown to stick to transcription factors and inhibit the normal process for manufacturing cell proteins.

The investigators also note that the same mechanism of transcription factor interference likely operates in a second form of myotonic dystrophy that was identified by MDA researchers in 2001. This form, type 2 myotonic dystrophy, stems from an elongated stretch of DNA on chromosome 3.

“ There’s a unifying appeal to this discovery, if it ultimately proves to be the primary mechanism of the disease,” Junghans said. “Most genetic diseases are defined by a defect in a particular protein. In the myotonic dystrophies, however, it’s been very hard to track down the protein defects that cause the multitude of abnormalities.

“ When we know better which affected transcription factors are most critical, gene therapy may be possible to give extra transcription factors. This could restore proper synthesis for many proteins at once, and, one hopes, restore the health of the muscle or other tissue.”
MDA is a voluntary health agency working to defeat more than 40 neuromuscular diseases, including the muscular dystrophies, through programs of worldwide research, comprehensive services, and far-reaching professional and public health education.