Researchers have discovered the chemical defect that causes the most common and deadly form of muscular dystrophy--a giant step toward a treatment for a disease that cripples up to 50,000 young men and boys in the United States.
Victims of this hereditary disease lack a key protein that helps trigger muscle contraction, the scientists said. The absence of this protein sets off a chain of events in the muscle cell that leads to destruction of cells and the loss of muscle strength.
The finding "tells us exactly what it is that needs to be corrected in order to develop treatment for the disease," said Donald S. Wood, director of research at the Muscular Dystrophy Assn., which helped finance the research.
The protein's discovery was announced in papers being published this week in Cell and Nature, two science journals.
The announcement coincided with the publication of a third paper reporting the discovery of another protein that plays a key role in the contraction and relaxation of muscles. Researchers suspect, but they are not certain, that this protein may play a role in other forms of muscular dystrophy.
In any case, its discovery promises to give scientists a much better understanding of how muscles work. This knowledge could lead to new therapies for a variety of muscle diseases, such as amyotrophic lateral sclerosis (Lou Gehrig's disease) or cerebral palsy, experts said.
"We've never had a more exciting time than right now," Wood said.
The most serious form of muscular dystrophy, called Duchenne muscular dystrophy, strikes one in every 3,500 males born.
The disease, which rarely affects females, is usually diagnosed between ages 3 and 5 when muscle weakness develops. The continuing loss of muscle strength almost always leaves victims wheelchair-bound by age 11 and usually results in death before age 30 due to respiratory failure.
(There is no therapy for muscular dystrophy. But in August, researchers at Johns Hopkins University and Washington University reported that, in two studies involving 49 boys, a steroid hormone, prednisolone, delayed the onset of the disease in all the boys. Unfortunately, the hormone caused severe side effects, including sharp weight gains, cataracts and osteoporosis.)
The Duchenne muscular dystrophy protein, named dystrophin, was identified by a group of researchers led by pediatrician Louis Kunkel of Children's Hospital of Boston.
The breakthrough was made possible by Kunkel's identification in 1986 of a part of the defective gene that causes Duchenne muscular dystrophy. From this genetic information, he made a calculated guess that paved the way for his momentous discovery.
At the time, Kunkel knew that the defective gene was the blueprint for a particular component of the diseased muscle cell, a protein. But he did not know if that protein was actually present or, if it was, where in the cell the protein was located.
Kunkel thought that by ascertaining the protein's presence and location he could deduce its function, which would give a clue to the biochemical mechanism for muscular dystrophy.
He set out to test his supposition by predicting part of the composition of dystrophin. Based on this prediction, he synthesized part of the protein and injected it into sheep and mice. Immediately, the animals' immune systems produced antibodies against the substance.
The antibodies served as a tool to detect the presence and location of dystrophin.
If the protein is present, the antibodies will bind to it; if not, the antibodies will be washed away.
Using this approach, Kunkel's group found that dystrophin was not present in muscle cells from two boys with Duchenne muscular dystrophy. Even though only two children were involved in this phase of the study, the finding was regarded as conclusive, Kunkel said. (The technique, now being applied to additional children, has been confirmed in mice with a Duchenne muscular dystrophy-like defect.)
In contrast, the protein was present in cells from healthy humans and mice.
The results indicate that the lack of the protein was probably the cause of Duchenne muscular dystrophy, Kunkel said.
To test this conclusion, researchers set out to determine dystrophin's location within the cell and hence its function.
They found that the protein is in the region of the muscle cell where an electrical impulse from the brain is converted into a chemical signal that causes the muscle to contract. When dystrophin is not present, Kunkel concluded, the muscle cells malfunction and eventually die.
Once dystrophin's role is known, he said, researchers can experiment with therapies to take its place or make its function unnecessary in Duchenne patients.
The protein is present in the cells in very small concentrations--0.002% of total muscle protein--which explains why it had not been observed before, he noted.