Muscular dystrophy gene cornered.

Muscular dystrophy gene cornered

After years of chasing down the exact location of the gene responsible for Duchenne muscular dystrophy (DMD), a devastating muscle-wasting disease afflicting thousands of U.S. males, medical researchers have it cornered. A team of six scientists from the Harvard Medical School in Boston report in the Oct. 16 NATURE that they now know about 10 percent of the DNA code associated with this gene. If all goes well, they say, they will decode the entire gene by the end of next summer. The scientists then will be able to predict what biological molecules are missing or defective in DMD patients, brightening the outlook for developing effective treatments.

Researchers have known for decades that among the 46 chromosomes in the nuclei of human cells, the X chromosome would be the one on which they would find the DMD gene. DMD is a sex-linked disease that affects half the sons of the female carriers. While the carriers themselves usually show no symptoms because they have a second, normal X chromosome, affected sons rarely live beyond their early 20s.

But the X chromosome is like a city with thousands of streets. To find the street on which the genetic trouble spot resides, scientists have used several clues. By comparing DNA from normal populations with DNA from DMD carriers and affected males, researchers found genetic markers that are in the vicinity of, and passed on with, the DMD gene (SN: 9/7/85, p.151). These markers are on the shorter of the X chromosome's two short arms. Another clue comes from microscope observations of the X chromosome of a boy suffering from three X-linked diseases, including Duchenne muscular dystrophy. A chunk in the middle of the same chromosomal arm was missing. Also, research done at several laboratories showed that all of the 13 women known to suffer from the disease had "breakpoints' in their second X chromosomes in the same location, designated by geneticists as Xp21 (SN: 11/10/84, p.293).

Still more evidence that Xp21 is the correct genetic street comes from single-stranded DNA probes that attach to and flag only those RNA or DNA sequences that are complementary with the probe. With the help of more than 20 laboratories worldwide, Louis M. Kunkel, leader of the Harvard research team, was able to report in the July 3 NATURE that probes made from specific DNA sequences within the Xp21 sector do not attach to the X chromosomes from a number of DMD-affected boys. This means these boys are missing DNA within that same sector of the X chromosome.

Now the six Boston researchers report for the first time about a tenth of the exact street addresses on Xp21 that together make up the DMD gene. They found that the same probes used to detect DNA deletions in DMD boys bind to parts of specific RNA isolated from fetal muscle tissue. The scientists are presently busy doing the laborious "door to-door' search of Xp21 to find more probes that do the same. Anthony P. Monaco, one of the researchers, says the RNA sequence probably codes for a protein important in muscle structures that are absent or defective in DMD. Those DNA probes that bind with the muscle-derived RNA will divulge the addresses that make up the remaining 90 percent of the gene's code.

Monaco says that spelling out the entire code should enable him and his colleagues to predict what protein the gene codes for. Specifically how this achievement might bear on potential treatments for muscular dystrophy is unknown, he adds. First, researchers will have to learn just how the protein fits into the complex biochemical fiasco that underlies muscular dystrophy.

But the more scientists know about the molecular events that orchestrate muscular dystrophy, the more rationally they can design therapies, says Donald Wood, associate director of research for the New York-based Muscular Dystrophy Association of America, which helped fund the research. He says the short-term possibility for treatment would be to supply the muscle cells of DMD patients with the specific protein coded for by the gene. Wood speculates that such a treatment might halt the progress of the disease, which otherwise would be invariable and relentless. Farther down the road, he says, it might even be possible to substitute a normal gene for the one deficient in DMD.