New Gene Found For Myotonic Muscular Dystrophy -- Unusual Mutation Involved

TUCSON, Ariz., Aug. 3, 2001 -- Researchers funded by the Muscular Dystrophy Association have identified a new genetic form of myotonic muscular dystrophy that may shed light on the nature of mutations causing this and perhaps other diseases.

"In addition to highlighting an unusual disease mechanism, the finding should also improve diagnosis of myotonic muscular dystrophy almost immediately, with better treatment strategies to follow," MDA Director of Research Development Sharon Hesterlee said.

Myotonic muscular dystrophy (DM, MMD or Steinert's disease) is the most common adult form of muscular dystrophy, affecting more than 30,000 Americans. Unlike most forms of muscular dystrophy, which primarily cause muscle weakness, DM also triggers a baffling array of other symptoms, such as hormonal problems, cataracts, heart disease and myotonia (difficulty relaxing muscles).

The genetic cause of the disorder has been equally frustrating to researchers who, with MDA funding, first identified the mutation responsible for one form of the disease, now called DM1, in 1992.

The mutation turned out to be an expanded sequence of DNA in the DMPK gene on chromosome 19. Surprisingly, the mutation occurs in an "untranslated" region of the gene - an area that doesn't actually spell out any portion of the DMPK protein (a protein important to muscle function).

This odd finding puzzled scientists, who had previously been accustomed to finding disease-causing mutations in the "translated" regions of genes - those regions that spell out instructions for protein components.

Researchers have since debated three possible interpretations of the DM1 results: Are disease symptoms caused by a reduced amount of the DMPK protein itself? Does the expanded DNA segment somehow affect the activity of unrelated but adjacent genes? Or - a relatively new idea - does the mere presence of the expanded segment in RNA (the intermediate between DNA and protein) contribute to the disease? All three mechanisms seem to be operating in DM1.

While the debate about DM1 went on, neurologist John Day and molecular geneticist Laura Ranum of the University of Minnesota's Institute of Human Genetics noted that many patients at their clinic in Minneapolis who had the full range of DM symptoms didn't have the DMPK mutation at all. In 1998, they named this form of the disease DM2 and localized the genetic cause to a region of chromosome 3. It seems to be most common in people of German descent.

In the current study, appearing in today's issue of Science, Ranum, Day and colleagues from Minnesota, Texas and Germany have identified the precise DM2-causing mutation. The mutation is in an untranslated region of DNA on chromosome 3 - this time in an "intron" of a gene called ZNF9.

The introns are "untranslated" parts of genes that are removed completely before protein production. The researchers don't think the ZNF9 protein is affected by the mutation.

"This finding suggests that both diseases are caused by abnormal RNA containing expanded repeats rather than by the proteins encoded by the genes harboring the mutations," Ranum said.

Ranum said today's finding confirms the speculation that abnormal RNA in and of itself can contribute to a disease, without always affecting the protein. The finding may elucidate the mechanism underlying other genetic disorders, including some forms of the neurological disease spinocerebellar ataxia.

"We now have evidence that excess RNA itself probably causes the complex features of myotonic dystrophy," Day said. "This understanding will undoubtedly help us to develop treatments to control these devastating and potentially fatal disorders."

MDA is a voluntary health agency working to defeat more than 40 neuromuscular diseases through programs of worldwide research, comprehensive services, and far-reaching professional and public health education. The Association's programs are funded almost entirely by individual private contributors.

For more information, call MDA at (800) 572-1717 or go to www.mda.org.