Cholesterol clutter. Cholesterol (blue) builds up in cells that have a defective NPC1 gene.

Newfound Disease Gene Holds Key to Cholesterol Traffic

Scientists have tracked down the gene for a fatal disorder of the nervous system that strikes in childhood. The find, reported in tomorrow's issue of Science, not only gives hope to those searching for a treatment or cure for Niemann-Pick type C disease, but also may help researchers understand how normal cells process cholesterol.

Because the cells of Niemann-Pick patients cannot process cholesterol, they become glutted with the fatlike molecule. Nerve cells die first, leading to problems seeing, walking, hearing, and swallowing. Now a team of some three dozen investigators reports that the culprit is a mutation in a gene for a protein called NPC1. Normally, NPC1 appears to sense a cell's level of cholesterol and help shuttle it from one part of the cell to another. In Niemann-Pick disease, it seems, the defective protein hampers the cholesterol's movement and the feedback mechanisms that normally control its level.

Led by cell biologist Peter Pentchev of the National Institute of Neurological Disorders and Stroke and Danilo Tagle of the National Human Genome Research Institute (NHGRI), the team homed in on the gene by looking for inherited genetic markers in several afflicted families. This hunt gave a boost to another quest that had been under way for 2 years: finding the gene defect in mutant mice that show the same symptoms as Niemann-Pick patients. By combining data gathered from mouse breeding studies with information about the gene's location in humans, molecular biologist William Pavan of NHGRI and his colleagues were able to locate the mouse gene and confirm that it was identical to the human gene. They, too, report their findings in tomorrow's Science.

The similarity of the mouse and human genes means researchers will have a relevant animal model for the disease. But the implications of the NPC1 protein will go far beyond Niemann-Pick disease, says Laura Liscum, a cell biologist at Tufts School of Medicine in Boston. "It's a protein that's screaming for attention." Sorting out its role "will be central to understanding the process of how cells deal with cholesterol," says Joseph Goldstein of the University of Texas Southwestern Medical Center in Dallas, who shared a Nobel Prize for studies of cholesterol regulation.

Posted in Biology