The findings are reported by National Institutes of Health (NIH)
scientists from the National Center for Human Genome Research (NCHGR) and
the National Institute of Neurological Disorders and Stroke (NINDS), in
collaboration with researchers from the UMDNJ-Robert Wood Johnson Medical
School in New Brunswick, New Jersey, and the Istituto de Scienze
Neurologiche in Naples, Italy.
"This exciting result gives us a powerful new tool to understand why
nerve cells die in Parkinson's disease and how to stop them from dying.
It will usher in a new era of Parkinson's disease research," says NINDS
Director Zach Hall, Ph.D.
Efforts to locate the gene intensified after an August 1995 NIH-sponsored
workshop on Parkinson's disease at which scientists from NCHGR and NINDS
met Roger Duvoisin, M.D., of UMDNJ-Robert Wood Johnson Medical School.
Soon after, the NIH scientists, led by Mihael Polymeropoulos, M.D., of
NCHGR, began to carry out a genetic analysis of Parkinson's disease using
DNA from patients identified and followed by an international team led by
The impact of the current finding is to show that a single gene
alteration can cause the disease. The next step will be to find and
identify the specific gene involved, which is located somewhere within a
region of DNA on the long arm of chromosome 4. Learning the gene's exact
location and isolating it may eventually lead to genetic testing that
will help early
diagnosis and treatment. Learning what the gene is and how it works may
help researchers design treatments for all forms of Parkinson's
disease--not only inherited cases, but also those with no familial link
"We don't know that this gene affects all people with Parkinson's
disease, since we've only found it in one family," says Dr. Duvoisin.
"But this is a very important step. We now know what we have to do to
understand what causes the disease."
Until recently, most scientists believed the disease was due almost
exclusively to environmental factors such as drugs or toxic chemicals,
although in most cases, no environmental cause has been identified. But
many people appear to have an inherited susceptibility to the disease.
Studying a causative gene will help researchers discover how the disease
occurs and how to develop methods of preventing or curing the disease.
"Mutations in the gene located in this region will cause classical
Parkinson's disease, the very same symptoms commonly found in most people
with Parkinson's," says Dr. Polymeropoulos, lead author of the report.
"Understanding how that happens will help fit all the pieces of this
complicated disease together."
The researchers identified the gene region by studying the DNA of 28
members of a large Italian family containing almost 600 people. People
in this family, some of whom migrated to the United States between 1890
and 1920, can trace their ancestry to a single couple who lived in Italy
in the 18th century. More than 60 family members on both sides of the
Atlantic have been diagnosed with Parkinson's disease.
Dr. Duvoisin and his colleagues have studied the inheritance patterns of
Parkinson's disease for decades. In the 1980's, they began studying
families with multiple cases of the disease. They have now defined the
pattern of inheritance in 80 multicase families.
"Information on inheritance patterns of the disease opened the door to an
aggressive approach to understanding the genetics using the gene-finding
tools of the Human Genome Project," says Dr. Polymeropoulos. "Once we
started studying DNA from the families, we were able to map the gene in a
matter of weeks. Past disease-gene hunts have taken anywhere from years
The gene mutation in this family is inherited in a dominant fashion,
meaning that people who possess the mutation have a 50 percent chance of
passing it on to their children. Only one parent must carry the mutation
for the disease to appear in a couple's offspring. The symptoms of
familial Parkinson's are identical to those in families with no history
of the disease, except that the inherited form sometimes develops earlier
Symptoms of Parkinson's disease include tremor (particularly tremor of a
body part at rest), stiff limbs, slow or absent movement, lack of facial
expression, a shuffling gait, and a distinctive stoop. Other symptoms,
such as depression and impaired ability to think may also
develop, especially during the later stages of the disease. These
symptoms result from degeneration of nerve cells in the brain. The
withered cells fail to release dopamine, one of the neurotransmitters, or
nerve signaling chemicals, crucial for communication between nerve cells.
To learn what percentage of Parkinson's disease patients possess an
alteration in the chromosome 4 gene, Dr. Polymeropoulos and his
colleagues plan to study additional families with several affected
individuals to see if they carry the distinctive marker in the same
region on chromosome 4. Although many families have more than one member
with Parkinson's disease, "there are not very many of the size of the
family that we used, so it may be a question that will take some time to
answer," says Dr. Polymeropoulos. Families with different inheritance
patterns may have mutations that are different from the one found in the
"Even with a relatively common disease like Parkinson's, it is rare to
find families or situations that give us such particular insight and
research power," says Robert Nussbaum, M.D., Chief of NCHGR's Laboratory
of Genetic Disease Research. "We need the help of the public, as well as
physicians who are out there taking care of those patients, to keep their
eyes open for these unusual situations which can be so helpful in
furthering our research."
The long list of people with Parkinson's disease includes evangelist
Billy Graham, science journalist Earl Ubell, and Attorney General Janet
Reno. Many other people, including the former boxer Muhammed Ali, have
Parkinson's-like symptoms due to head injury, toxic chemicals, or other
problems. Another Parkinson's-like disorder, Wilhelmsen-Lynch disease
(disinhibition-dementia-parkinsonian-amyotrophy complex), has been linked
to a region of chromosome 17. A defect in mitochondrial DNA, which is
separate from a person's chromosomes, was recently linked to sporadic
Parkinson's disease with unusual symptoms. Other genetic mutations may
also play a role in some cases.
The NCHGR oversees NIH's role in the Human Genome Project, an
international research effort to develop tools for gene discovery. The
NINDS is the nation's leading supporter of research on the brain and
nervous system and a lead agency for the Congressionally-designated
Decade of the Brain.
1Polymeropoulos, M.H.; Higgins,J.J.; Golbe,L.I.; Johnson, W.G.; Ide, S.E.; Di Iorio G.; Sanges, G.; Stenroos, E.S.; Pho, L.T.; Schaffer, A.A.; Lazzarini, A.M.; Nussbaum, R.L.; Duvoisin, R.C. "Mapping of a Gene for Parkinson's Disease to Chromosome 4q21-q23." Science, Vol. 274, November 15, 1996 (pp. 1197-1199).