 Bethesda,
MD (11 July 1997) The identification of a genetic flaw associated with
a rare inherited childhood disease could lead to treatments for the
disorder, as well as better understanding of how the body processes cholesterol.
Scientists at the National Institutes of Health have identified a gene
alteration associated with the fatal childhood cholesterol disorder Niemann-Pick
type C (NPC). The disease is characterized by progressive deterioration
of the nervous system. Symptoms including enlarged spleen and liver, poor
muscle control, slurred speech and dementia begin to manifest when
low-density lipoprotein (LDL)-derived cholesterol (aka "bad" cholesterol)
accumulates in lysosomes found within cells of the brain, liver, spleen,
lungs, and bone marrow.
The cause of the disease has been traced to a gene, known as NPC1,
located on human chromosome 18. A malfunction in the gene impairs
the normal movement of cholesterol within cells.
"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."
For example, the finding may contribute to the understanding of atherosclerosis,
a leading cause of death in the US and throughout the world. Atherosclerosis
is an accumulation of fatty tissue inside arteries that blocks blood flow,
leading to heart disease and stroke.
Moreover, 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.
The researchers hope the new finding will be 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."
NPC is extremely rare, affecting some 300 young people in the US. The
disorder 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.
"The identification of this gene, the fruit of a successful partnership
between
scientists and families, is a significant step in NPC research," says
senior researcher Dr. Tagle. "Our search was greatly accelerated by the
tools and resources provided by the Human Genome Project. 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 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.
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, the researchers
note.
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 new research appears in the July 11, 1997, issue of the journal
Science.
Related information on the Internet
Niemann-Pick
Disease Fact Sheet
AE:
Ethics of Genetic Screening
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