New mouse marks latest stride in muscular dystrophy research

September 06, 2000

Most days, neurologist Charles Thornton, M.D., spends some time away from his patients and heads for the laboratory, where he works with mice. It might seem an unlikely action for a doctor ultimately concerned with human health. But his forays in the laboratory have helped Thornton and his team develop a new kind of mouse that may someday help doctors around the world treat patients with myotonic dystrophy, the most common form of muscular dystrophy in adults.

Thornton's team at the University of Rochester has generated mice with symptoms that mimic those of patients with myotonic dystrophy. The mice provide the first animal model for a disease that affects about 40,000 Americans. Already, research with the mice has pointed to an unexpected disease-causing role for a molecular messenger, mRNA, that has long been considered simply an information carrier, not a trouble maker. The team's results appear in the Sept. 8 issue of Science.

"Why all the fuss over mice?" asks Thornton. "Well, it is possible to test dozens or even hundreds of potential treatments in mice in a short span of time. Without an animal model, it takes several years and some risk to test just one treatment in people. I'm hopeful that these mice will accelerate the discovery process."

Myotonic dystrophy is a disease marked by progressive muscle weakness. Oftentimes patients first notice something's wrong when the muscles in their hands become stiff; sometimes they have a hard time letting go when they shake another person's hand. Their muscles become steadily weaker and waste away, and eventually many patients have difficulty walking, swallowing, and breathing. The disease also affects the eyes, the heart, and the brain.

Currently there is no treatment, and physicians don't really understand how the disease occurs. In 1992 researchers got a boost when they discovered the genetic defect on chromosome 19 that causes myotonic dystrophy. But that knowledge hasn't helped them understand the disease as much as they had hoped, and more than a dozen attempts by scientists around the world to make mice with symptoms of the disease have fallen short.

"A lot of effort is aimed at finding the abnormal genes that cause diseases. In some cases, discovering one of these genes can provide instant insight into what causes disease. But sometimes, as in this case, lots of additional work is necessary," says Thornton, associate professor of neurology.

Thornton's mice are the first to recreate the muscle stiffness that is central to the disease. To develop the mice, the team added into mouse chromosomes a particular gene fragment like the genetic abnormality that causes human disease. In healthy people, the gene that can cause the disease has five to 30 copies of a "triplet repeat," a sequence of the same three chemical bases repeated over and over. In people with myotonic dystrophy, that sequence is repeated hundreds or thousands of times in a kind of molecular stutter. A similar type of mutation is also at the root of several other diseases, including Huntington's disease and Fragile-X syndrome, a common cause of mental retardation.

The new mice have already provided researchers with a surprise that may have implications for other diseases. The team showed that messenger RNA (mRNA), long considered simply a way to move key genetic instructions out of the cell's control center in the nucleus, itself seems to be responsible for the symptoms of myotonic dystrophy in mice. Faulty messenger RNA accumulates in the nuclei of cells in the muscles of the mice, clumping together and somehow damaging muscle fibers.

"Normally," says Thornton, "messenger RNA transmits genetic information out of the nucleus and into the main part of the cell where its instructions are carried out. That's its only job. In this case, it seems to stay in the nucleus, and it's doing something entirely different that's harmful. The messenger itself is actively making cells sick."

Thornton's team is trying to figure out exactly how the clumps of mRNA hurt cells. RNA molecules can be large, convoluted molecules with more loops and turns than any roller coaster, and it's possible that the molecules are getting in the way of other proteins that normally travel within the nucleus to do their jobs. Or the extra mRNA may latch onto other molecules and prevent them from attaching where they should.

It's common for faulty genes to cause disease. Usually, a faulty gene results in too much or not enough of a certain protein, in a protein that cannot do what it was designed to do, or in a protein that knocks out other genes or proteins. But scientists have found that these straightforward explanations do not seem to hold when it comes to myotonic dystrophy. Mice with an abnormal protein product of the myotonic dystrophy gene share only a few of the symptoms that affect people with the disease.

"Every other human genetic disease that we know of is caused by abnormalities ultimately in the proteins that the genes code for. A faulty mRNA that actively causes disease seems to go against genetic dogma," Thornton says. His team is continuing to look at possible ways that mRNA might damage muscles.
Thornton is co-director of the Neuromuscular Disease Center, an internationally recognized center for care and research on diseases like muscular dystrophy and Lou Gehrig's disease. In addition to clinical trials involving human patients, he hopes to begin testing potential new treatments in mice within a few months. Thornton's group is making the animals available to researchers at other centers throughout the world for their research projects.

Also taking part in the research are neurologists Ami Mankodi and Eric Logigian, instructor Linda Callahan, and technical associates Carolyn McClain, Robert White, Don Henderson and Matt Krym. This work was supported by the Muscular Dystrophy Association, the American Federation for Aging Research, and the Saunders Family Neuromuscular Research Fund, funded by Rochester businessman Phillip Saunders and his family.

University of Rochester

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