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NIH Scientists Identify Gene for Fatal Childhood Disorder, Niemann-Pick Type C

Finding Points to Critical New Steps in Cholesterol Processing

July 1997

Science Magazine CoverBETHESDA, Md. -After decades of work, scientists at the National Institutes of Health (NIH) have identified a gene alteration associated with the fatal childhood cholesterol disorder Niemann-Pick type C (NPC). Learning how the gene functions may lead to the first effective treatment for the disease and to a fundamental new understanding of how cholesterol is processed in the body.

The gene, known as NPC1, is located on human chromosome 18. NPC causes progressive deterioration of the nervous system by blocking the movement of cholesterol within cells. The finding opens the door to improved diagnosis and understanding of this neurological disorder, which is usually fatal by age 25, and to the design of therapies that may correct the underlying problem. The finding also may contribute to the understanding of atherosclerosis, a more common killer associated with cholesterol buildup. Atherosclerosis is an accumulation of fatty tissue inside arteries that blocks blood flow, leading to heart disease and stroke.

"This discovery is an excellent example of how research on rare brain disorders often pays off in other ways," says Zach W. Hall, Ph.D., director of the National Institute of Neurological Disorders and Stroke (NINDS). "By identifying this gene, we not only take a crucial step forward in understanding this devastating disorder, but also gain insights into problems that affect every one of us."

The NPC1 finding is the first step toward developing a cure for NPC. "This gene reveals a new way that cells handle cholesterol," says Peter G. Pentchev, Ph.D., of NINDS. "It provides a fundamental understanding of a previously undefined pathway of cholesterol metabolism. Like motor mechanics, we have to know what's wrong before we can fix it."

Dr. Pentchev and his colleagues at NINDS have studied NPC for almost 20 years. Other key members of the team that identified the human gene include Eugene D. Carstea, Ph.D., formerly of the NINDS; Jill A. Morris, Ph.D., of NINDS; and Danilo A. Tagle, Ph.D., and Melissa Ashlock, Ph.D., of the National Human Genome Research Institute (NHGRI).

Collaborating scientists, led by William J. Pavan, Ph.D., of NHGRI, identified the same gene in a mouse model for NPC. The human and mouse gene findings appear in back-to-back reports in the July 11, 1997, issue of the journal Science.

NPC develops when a person receives two altered copies of the gene -- one from each parent. Carriers of the disease, who possess a single copy of the altered gene, sometimes develop subtle abnormalities in cholesterol metabolism. However, they remain healthy, and most do not know they are carriers until they have an affected child. NPC often appears at random in families with no history of the disorder, and it occurs in individuals from many ethnic groups.

Approximately 300 Americans are afflicted with NPC, in which low-density lipoprotein (LDL)-derived cholesterol accumulates in digestive compartments called lysosomes that are found within cells of the brain, liver, spleen, lungs and bone marrow. LDL is the so-called "bad" cholesterol molecule linked to atherosclerosis. Symptoms of NPC usually appear in early childhood and typically include an enlarged spleen and liver, poor muscle control, impaired eye movements, slurred speech, and dementia. Drugs can control some symptoms of NPC, and laboratory studies suggest that low-cholesterol diets and cholesterol-lowering drugs might be beneficial. However, there is no proven treatment that can slow the course of the disease.

"The identification of this gene, the fruit of a successful partnership between scientists and families, is a significant step in NPC research," said Dr. Tagle, senior author of the human gene paper. "Our search was greatly accelerated by the tools and resources provided by the Human Genome Project (HGP). Moreover, our findings shed new light on how cells metabolize cholesterol that may be different from pathways involved in cardiovascular diseases and provide insights on how cholesterol affects brain functions."

The discovery of the NPC1 gene will improve scientific understanding of how cells process and transport cholesterol within the cell. Since the NPC1 gene affects the brain, it also may provide insight about how cholesterol affects brain development and the formation of myelin, a fatty substance that improves transmission of nerve signals.

Although the researchers do not know precisely how it works, the NPC1 protein is similar in structure to several other proteins involved in cholesterol regulation. The protein is also similar to proteins found in yeast and worms, suggesting that it is important for survival because it has remained largely unchanged throughout millions of years of evolution. The protein's presence in these organisms makes them a powerful resource for testing new therapies and learning how the protein works.

Inserting copies of the NPC1 gene into cultured skin cells from NPC patients corrects the abnormal cholesterol buildup, suggesting that gene therapy might eventually be able to cure the disease. The first step to successful gene therapy, however, is for scientists to find better ways to insert genes into cells of the brain, where the worst symptoms of NPC arise. It may also be possible to use drugs to reverse the abnormal cholesterol storage.

"Researchers should be able to test new therapies relatively quickly because they already have a mouse model with the mutated gene," said Dr. Pavan, senior author of the mouse gene report. "Usually, scientists must spend time creating animal models with the mutated gene after the human gene is discovered."

The NIH researchers located NPC1 by a combination of approaches, including conventional positional cloning techniques and a strategy using yeast artificial chromosomes (YACs) containing large pieces of human DNA, to narrow the region likely to contain the gene. To date, the researchers have identified eight different NPC1 mutations in nine unrelated NPC families. They hope to link specific mutations to differences in the way the disease manifests itself in particular patients, such as age of onset.

"In spite of the wide variety of mutations, the discovery of the gene will now enable the development of genetic tests for prenatal diagnosis and assessment of carrier status in families affected by this devastating disorder," said Dr. Carstea. Dr. Carstea recently left the NINDS, where he headed the gene-cloning collaboration, to take up a new post as Director of the Saccomano Research Institute at St. Mary's Hospital, Grand Junction, Colorado.

While 95 percent of the NPC families tested so far have mutations in the NPC1 gene, the disease in some families shows no correlation with chromosome 18. This means there must be a second NPC gene on another chromosome. This gene probably controls another step in the newly identified cholesterol pathway that goes awry in NPC, said Dr. Pentchev. The researchers now plan to focus on locating the second NPC gene and analyzing how different mutations affect the onset and symptoms of the disease.

Researchers from the Czech Republic, France, Israel, New Zealand, Japan, the Netherlands and several U.S. institutions, contributed to these findings by sharing data and cell lines from affected families. The Niemann-Pick Foundation of the United Kingdom also helped the effort by locating families afflicted with the disorder. The investigators received major financial support for this work from the Ara Parseghian Medical Research Foundation and from the National Niemann-Pick Disease Foundation.

"Because of the dedication of the researchers and generous donations from people all over the world, we have been able to accomplish the isolation of the gene responsible for NPC. This was our first goal when we started the Ara Parseghian Medical Research Foundation two and a half years ago," said Ara Parseghian, former head football coach at the University of Notre Dame in Indiana. Coach Parseghian's three youngest grandchildren suffer from NPC. His grandson, Michael, died this past March, four days before his tenth birthday. Michael's two sisters suffer from various stages of the disorder.

"We have the ball, now we have to make it down the field and into the end zone. We can only win this fight by finding out why the gene acts the way it does. And finally, we want to achieve the ultimate victory -- a cure for NPC. This is a race against time to save all children afflicted with this terrible disease," said Coach Parseghian.

The NINDS and the NHGRI are part of the National Institutes of Health (NIH) located in Bethesda, Maryland. NINDS is the nation's leading supporter of research on the brain and nervous system and a lead agency in the Congressionally designated Decade of the Brain. The NHGRI is a major partner in the Human Genome Project, an international research effort to map the estimated 50,000 to100,000 genes and read the complete set of genetic instructions encoded in human DNA.

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Last updated: July 01, 2006