MDA RESEARCHERS DEVELOP MOUSE WITH MUSCLE DISEASE AND CLUES TO UNUSUAL GENETIC FLAW

TUCSON, Ariz., Sept. 8, 2000 -- Researchers at the University of Rochester (N.Y.) School of Medicine and Dentistry have, for the first time, developed a mouse with symptoms of myotonic muscular dystrophy (MMD), a genetic disorder affecting muscles and other organs, the Muscular Dystrophy Association announced today.

The mouse is expected to lead to better understanding of and eventually to better treatments for this disabling disease, the most common adult form of muscular dystrophy. It's also expected to give biologists a better grasp of the type of genetic defect that underlies this and several other genetic disorders.

Neurologist Leon Charash, who chairs MDA's Medical Advisory Committee, said, "Mouse models like this one allow you to try out medications, gene transfer experiments and cellular manipulations to see if they help or harm before any patient is subjected to them. I'm thrilled that we now have this model of the muscle effects of myotonic dystrophy."

The research team was led by MDA-funded researcher Charles Thornton, associate professor of neurology at the University of Rochester School of Medicine, and included MDA research grantee Ami Mankodi, also a neurologist at that institution.

Thornton, co-director of the MDA clinic at the university's medical center, said, "The idea behind this project was very unconventional. It wasn't easy to get support for it, which makes us especially grateful for the support that we received from MDA.

"Now we're one step closer to understanding what causes the muscle weakness in myotonic dystrophy," he added. "I'm hopeful that this work will stimulate additional research and help us find better treatments."

The team published its findings in today's issue of the journal Science.

Myotonic muscular dystrophy, which affects one in 7,400 people worldwide, is the most common muscular dystrophy in adults, although it also affects children. It's known as a muscular dystrophy because of its effects on muscle, but the disease also affects many other organs. The muscle effects include progressive weakness, particularly of the face, neck, lower arms, lower legs and respiratory muscles. The disease is also characterized by myotonia, an inability to relax muscles at will.

The nonmuscle effects include cardiac rhythm abnormalities; cataracts, which can interfere with vision; gastrointestinal disorders; complications in pregnancy and delivery; early baldness in men; and neuropsychiatric effects, such as excessive sleepiness and emotional flatness.

There's no treatment to stop the muscle deterioration, but symptoms can be treated with cardiac pacemakers, ventilatory support for failing respiratory muscles, bracing of limb muscles and cataract surgery.

Myotonic dystrophy is an autosomal dominant genetic disorder, meaning both sexes can have it and that only one parent need pass on the genetic defect for a child to develop the disease.

MDA-supported researchers were among those who first identified the unusual genetic defect underlying myotonic dystrophy in 1992. The defect, known as an "expanded triplet repeat," is known to be the genetic culprit in only a handful of diseases. Among those are Huntington's disease and several forms of inherited ataxia (incoordination).

The defect in myotonic dystrophy is unusual because it occurs in the "untranslated" part of a gene's DNA, the area that doesn't end up as part of the instructions for a cellular protein. Instead, the expanded DNA affects only itself and the next biochemical step toward protein synthesis, which is known as RNA.

The mouse model Thornton's team constructed can be used to investigate how the DNA and RNA abnormalities affect muscle function. The team believes the problem may result from an accumulation of RNA in the cell's control center, the nucleus.

The mice also have an expanded triplet repeat, but the defect was inserted into a different gene from the one that carries it in human myotonic dystrophy cells. Instead of the gene known as DMPK, which has the defect in people, the gene for alpha-actin was chosen to carry the defect in the mice.

The researchers chose a gene that's highly active only in muscle cells and inactive in other kinds of cells. That way, Thornton explains, they were able to isolate the muscle effects and study them separately from other complications of the disease, some of which have in previous studies interfered with the fertility and viability of the mice.

The team also wanted to test whether the expanded repeat would cause the muscle-related effects even if it were inserted into a gene other than the one involved in human disease. The answer appears to be yes, Thornton says, noting that the study shows that expanded triplet repeats in the RNA can lead to malfunction of muscle cells, and that the effect is probably independent of which gene harbors them. This finding is considered of fundamental importance in understanding the pathology of triplet repeats and the disorders they cause.

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.

MDA annually funds some 400 scientific research teams. These investigators have made significant advances toward cures for several muscle-wasting diseases.