Single copy of Parkinson's-risk gene
mutation may lead to earlier symptom onset
BOSTON - June 12, 2006 - Mutations in a gene already known
to play a role in causing an inherited form of Parkinson disease
may also influence the age at which symptoms of the neurological
disorder appear. While inheriting two abnormal copies of the parkin
gene previously had been associated with the development of early-onset
Parkinson's, a new study from a multi-institutional team led by
Massachusetts General Hospital (MGH) researchers finds that even
a single mutated copy of parkin reduces the age of onset
of the disease. The findings appear in the June Archives of Neurology.
"This study reinforces the fact that there are multiple mechanisms
behind Parkinson disease and will lead us to examine other pathways
with which parkin interacts," says James Gusella, PhD,
director of the MGH Center
for Human Genetic Research, the study's senior author. The report
is part of the larger GenePD
project, an international collaborative study of siblings with
Parkinson disease, which is based at Boston University Medical Center
and led by Richard Myers, PhD.
Parkinson disease is a neurodegenerative disorder characterized
by tremors, rigidity, difficulty walking and other symptoms. It
is caused by the destruction of brain cells that produce the neurotransmitter
dopamine and is the second most common neurodegenerative disorder.
The condition's prevalence increases with age - appearing in 1 percent
of those over 60 and 4 to 5 percent of those over 85 - but it can
develop in much younger patients. While the cause of most cases
of Parkinson's is unknown, there are rare, inherited forms. Five
genes have been identified as increasing the risk for Parkinson's
- parkin mutations inherited from both parents being the
most common genetic cause of early-onset disease - but additional
susceptibility genes are yet to be found.
Since finding new genes is a goal of the GenePD study, a preliminary
step is to identify those whose familial Parkinson's can be attributed
to one of the known genes. Focusing on parkin, the researchers
began by analyzing samples from 329 families with at least two affected
members, collected from 20 sites in North America, Europe and Australia.
From this collection, samples from two groups of families were selected:
those in which affected siblings have inherited identical versions
of the chromosome 6 region in which parkin resides and those
in which at least one affected member developed symptoms before
age 54, since early-onset Parkinson's involves symptoms appearing
before the age of 50.
For each of the 183 families selected, complete genetic screens
were done on the patient with the earliest onset of symptoms. If
that patient was found to have parkin mutations, genetic
screens were completed on other affected family members. Parkin
mutations were found in 23 (12.6 percent) of the 183 screened families.
Among the families with parkin mutations, 13 had at least
one member with mutations on both copies of the gene, while in 10
families affected members had a single mutated copy of parkin.
Eighteen different parkin mutations were identified, four
of which had not previously been described.
The average age of onset in all those with parkin mutations
was about 43. But among the families in which the parkin
chromosome markers were identical, those with no mutations in the
gene developed symptoms at an average age of about 61, those with
a single abnormal copy of parkin at around age 50, and those
who inherited two mutated copies had onset at around age 36.
"This is the first time anyone has shown that a single parkin
mutation can lower the age of onset," Gusella says. "We
don't know if that would be sufficient to cause the disease. It's
more likely that these mutations increase susceptibility to other
factors underlying the development of Parkinson's. The result also
lets us know that future researchers shouldn't just study the effects
of completely knocking out the parkin gene, we'll need to
examine knocking out a single copy as well," he adds. Gusella
is the Bullard Professor of Neurogenetics at Harvard Medical School.
Co-authors of the report at MGH are first author Mei Sun, MD, PhD;
John Growdon, MD; Tammy Gillis, and Marcy MacDonald, PhD. Along
with Myers, co-authors at Boston University School of Medicine are
Jeanne Latourelle; Ranjana Prakash; Sally Williamson; Gang Xu, PhD;
Jemma Wilk, DSc; Marie Saint-Hilaire, MD; and Anita DeStefano, PhD.
The study was supported by grants from the Bumpus Foundation and
the U.S. Public Health Service.
Additional co-authors are Frederick Wooten, MD, University of Virginia;
Mark Lew, MD, University of Southern California; Christine Klein,
MD, University of Lubeck, Germany; Lawrence Golbe, MD, and Margery
Mark, MD, University of Medicine and Dentistry of New Jersey - Robert
Wood Johnson Medical School; Brad Racette, MD, and Joel Perlmutter,
MD, Washington University School of Medicine, St. Louis; Garth Nicholson,
PhD, University of Sydney, Australia; Carlos Singer, MD, University
of Miami, Florida; Ray Watts, MD, University of Alabama at Birmingham;
Peter Pramstaller, MD, General Regional Hospital, Bolzano, Italy;
Scott Sherman, MD, University of Arizona; Irene Litvan, MD, University
of Louisville School of Medicine; Holly Shill, Barrow Neurological
Institute, Phoenix, Arizona; Abbas Parsian, PhD, University of Arkansas
for Medical Sciences; Mark Guttman, MD, University of Toronto; Oksana
Suchowersky, MD, and Nancy Labelle, BN, University of Calgary; Sefano
Goldwurm, MD, PhD, and Gianni Pezzoli, MD, Instituti Clinici de
Perfezionamento, Milan; Kenneth Baker, PhD, Cleveland Clinic Foundation;
David Burn, MD, and Patrick Chinnery, MD, Newcastle General Hospital,
England; and Peter Vierette, MD, Klinikum Lippe-Lemgo, Lemgo, Germany.
Massachusetts General Hospital, established in 1811, is the original
and largest teaching hospital of Harvard Medical School. The MGH
conducts the largest hospital-based research program in the United
States, with an annual research budget of nearly $500 million and
major research centers in AIDS, cardiovascular research, cancer,
computational and integrative biology, cutaneous biology, human
genetics, medical imaging, neurodegenerative disorders, regenerative
medicine, transplantation biology and photomedicine. MGH and Brigham
and Women's Hospital are founding members of Partners HealthCare
HealthCare System, a Boston-based integrated health care delivery
Media Contact: Sue
McGreevey, MGH Public Affairs
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