Researchers Finally Discover Elusive Kidney Disease Gene By John Cramer Scientists have fully identified and begun exploring the function of the gene that causes most forms of polycystic kidney disease, the most common inherited kidney disease, according to a study by the American PKD1 Consortium, which includes researchers at the Johns Hopkins Medical Institutions, Integrated Genetics and Los Alamos National Laboratory. Now that researchers know where the gene is and what it does, the next step, they say, is determining how it works in order to devise a way to stop it from causing the disease, which affects 500,000 to 600,000 Americans. Their findings are reported in the April 1995 issue of "Human Molecular Genetics" and were presented at a Renal Cystic Disease Workshop sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases on March 31 at the National Institutes of Health. "We're still a very long way off from developing a clinical therapy, but this is an important step because it gives direction to scientists. We're not wandering blindly anymore," said Gregory G. Germino, principal investigator for the Hopkins group and assistant professor of nephrology. "One of the frustrations of those of us who care for people with PKD is the lack of therapies for preventing renal failure. Current treatments are limited to managing the complications. The major limitation has been our incomplete understanding of the nature and function of the PKD1 gene." Katherine W. Klinger, principal investigator for the Integrated Genetics genomics group and the company's vice president for science, said "Because this locus is so complex and duplicated, establishing the correct genomic sequence is key to understanding the pathogenesis of the disease. Now that the full-length sequence is identified, sorting out the causative defects will be our next challenge." Last year, scientists in Europe reported partial identification of the PKD1, or polycystic break point, gene when they discovered a chromosome break at one end of the gene responsible for most forms of polycystic kidney disease. This break disrupted the gene's usual function, allowing the pinpointing of the site on the gene where the mutation occurs. Extending this work, the American consortium, whose work was funded by the NIDDK, the Marion Merrell Dow/Polycystic Kidney Research Foundation Research Merit Award and the National Kidney Foundation, completed research about the gene's location and what it does by examining its molecular composition. This created a blueprint for understanding the biology and evolution of the gene, permitting the cloning and complete sequencing of the gene to begin analyzing why it mutates and how it functions. Sequencing is a chemical process in which the DNA molecule's base pairs are taken apart to determine their precise order along a segment of the molecule. The completion of the sequencing allows scientists to make the protein that the gene is coded for and study the protein's normal function and its role in the disease process. The European group identified 40 percent of the gene. The American consortium identified the remaining 60 percent, found sequencing differences in the part analyzed by the Europeans, and found sequences hinting that the gene works through receptors on kidney cells that bind with an unknown substance in the blood. The gene, however, is large and complicated, and extensive molecular studies are needed. "Once we determine how it functions, then we can start to explore therapies," Dr. Germino said. Polycystic kidney disease, one of the most common of all inherited diseases, causes renal failure by middle age in most sufferers. In some, it also causes cardiovascular complications.
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