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Scientists Isolate Dystrophy Defect

Three groups of scientists, including an MIT research team led by Professor David E. Housman, have linked a specific genetic defect to muscular dystrophy and, in a surprising discovery, have found that the genetic flaw can worsen with each generation.

Dr. Housman, professor of biology and a leading molecular geneticist, told The New York Times that this and other recent findings about generational changes in disease-causing inherited genes open up "moral, social and ethical problems that were totally unanticipated."

Until recently, it was assumed that genes, both normal and not, are handed down through generations essentially unchanged.

Now genetic counselors have to consider whether a flawed gene will not affect patients or even their children, but could cause a deadly disease in their grandchildren or great-grandchildren.

On the other side of the coin is the more hopeful possibility that mutant genes, in some circumstances, might gradually cure themselves over generations.

The three research groups that collaborated in linking a specific genetic abnormality to myotonic dystrophy-which affects one in 7,000 to 8,000 people worldwide as the most common type of muscular dystrophy-consisted of 39 scientists from 11 research centers in several countries.

The MIT scientists, who included postdoctoral researchers David Brook and Allen Buckler, teamed up with researchers from the Institute of Medical Genetics at the University of Wales College of Medicine in Cardiff to form one of the groups.

The overall effort was supported by the Muscular Dystrophy Association whose executive vice president and executive director, Robert Ross, said that the research results-reported in three separate papers in Nature, a British science journal, "demonstrated the benefits of scientific collaboration."

"With MDA's support they've shared their results and methods," he said, "allowing for rapid progress toward this impressive achievement. It brings us closer to a treatment for this baffling disease."

Dr. Housman said the MIT research also was supported by two National Institutes of Health programs, the Human Genome Initiative and the Program of Excellence of the National Heart, Lung and Blood Institute.

The basic finding of the scientists was that a segment of the gene, located on chromosome 19, is enlarged and unstable in people with myotonic dystrophy. The groups searched the chromosome in a coordinated effort, with two coming in at opposite ends of the suspect region and the third probing the center, according to the Times, which reported the discovery as its lead story.

The discovery gives investigators a precise way of diagnosing myotonic dystrophy-perhaps even before birth-by looking for the expanded genetic region.

And although researchers don't yet know how the identified genetic defect causes myotonic dystrophy, Dr. Leon Charish, chairman of the medical advisory committee of the Muscular Dystrophy Association, told the Times that scientists could soon learn exactly what defective chemical causes the disease's symptoms.

Molecular geneticist Pieter de Jong of the Lawrence Livermore Laboratory in Livermore, Cal., who led one of the research groups, said he also was confident the discovery will lead to the isolation of the gene and determination of the exact cause of the disease.

Also known as dystrophia myotonica and Steinert's disease, the disorder is a complex muscle disease affecting both men and women and usually appearing in adolescence or early adulthood. The disease may result in death in the 50s and 60s because of heart or respiratory failure.

Last year similar enlarged genetic segments were found to cause two other inheritable diseases, fragile X syndrome, a form of mental retardation, and spinal bulbar muscular atrophy, a rare wasting disease.

Dr. Housman told the Times that in these two diseases the expanding region of the gene consists of three nucleotides, the chemical building blocks of the gene, that even in normal individuals are repeated over and over again. In people with the disease, he said, the region starts growing out of bounds, creating a "replication catastrophe."

He said the same mechanism might underlie the expansion of the myotonic dystrophy gene and that once the process begins it continues with each generation, with the region growing bigger and bigger.

Dr. Housman said that some neurologists, based on what they have observed in their patients, reported that the disease seemed to grow worse with succeeding generations-but that geneticists until now dismissed the idea, arguing that it made no genetic sense.

The new discoveries, however, show that the neurologists were right, he told the Times, because the more the gene is expanded, the more severe the disease and the earlier its age of onset.

(This article is based on a story in The New York Times, an announcement by the Muscular Dystrophy Association, and conversation with Dr. Housman.)

A version of this article appeared in the February 12, 1992 issue of MIT Tech Talk (Volume 36, Number 20).

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