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| |  Epilepsy Gene Found STANFORD, Calif. -- March 25, 1996 -- Researchers have identified a gene that leads to epilepsy when a defective copy is inherited from both parents. The gene, when functioning properly, carries the instructions for a small protein called cystatin B. Knowledge of the gene will help doctors diagnose patients with a form of epilepsy called progressive myoclonus epilepsy, said the study's senior author, Dr. Richard Myers, associate professor of genetics at Stanford University School of Medicine. Correct diagnosis is especially important because phenytoin, a drug commonly used to treat some forms of epilepsy, can kill people with progressive myoclonus epilepsy, Myers said. The finding might also advance understanding of the causes of the more than 40 other known forms of epilepsy. "Any time you can find a genetic cause for a disease, even if it has multiple causes, you have the potential for understanding the biochemical pathway that gives rise to the disease. This same biochemical pathway might be involved in other forms as well," said Myers. Myers directs the Stanford Human Genome Center, a site of the federally funded Human Genome Project. The researchers describe the new finding in the March 22 issue of Science. A "Research News" article discussing the finding will run in the same issue. Myers' collaborators include the paper's first author, Stanford biological sciences graduate student Len A. Pennacchio; Stanford genetics professor Dr. David R. Cox; and Anna-Elina Lehesjoki and Albert de la Chapelle, both from the University of Helsinki, Finland. The Finnish researchers began studying this form of epilepsy about six years ago. They used information and blood samples from about 30 Finnish families to help locate the gene, narrowing its site to a segment of chromosome 21. Finns show a higher-than-average incidence of many genetic diseases because, compared with most other populations, they are relatively inbred, descended mainly from a small group that founded the population only 2,000 years ago. Progressive myoclonus epilepsy affects at least one in 20,000 people in Finland. It is diagnosed more rarely in the United States. In 1991, Stanford researchers joined the Finnish group in the search for the gene. They used data gathered through the Human Genome Project, which had already identified many genetic markers on chromosome 21. Genetic markers are distinctive DNA sequences that researchers can use as landmarks along the strand of DNA that makes up a chromosome. The scientists looked at the pattern of genetic markers in people with progressive myoclonus epilepsy and in their unaffected relatives. This comparison further narrowed the location of the gene to a region shared only by the people with the disease. This strategy, which incorporated several techniques (including one recently developed in Cox's laboratory), allowed the researchers to speed up their search by homing in more precisely on the gene's location. "Instead of looking through 2 million base pairs, we only had to look through 175,000. That made everything a lot easier," Myers said. Base pairs are the links making up a chain of DNA. The researchers found about a half dozen genes in the region, one of which -- the gene for cystatin B -- functioned abnormally in all of the blood samples from people with progressive myoclonus epilepsy. In these people, the gene failed to carry out its normal routine for producing cystatin B. "We sequenced this particular gene and found that people with the disease carried defective versions. This told us that mutations in this gene are responsible for this form of epilepsy," Pennacchio said. Cystatin B is a protein found in all human tissues. It is a member of a class of proteins called protease inhibitors, which regulate the activity of enzymes that degrade proteins. It was surprising to find that a protease inhibitor is involved in epilepsy, noted Pennacchio. "This will send researchers thinking in new directions," he said. "This is really an exciting time. This work is part of the payoff we are beginning to see with the progression of the Human Genome Project. It emphasizes the power of human genetics and its direct impact on human health and disease," Pennacchio added. "Now what's important is to figure out the function of the protein this gene makes. We need to understand why a deficiency in this protein -- cystatin B -- causes disease," Myers said. The research was sponsored by the National Institutes of Health, the Academy of Finland, the Sigrid Juselius Foundation and the Epilepsy Research Foundation of Finland.
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