September 3, 1997
Contact: Susan McGreevey
(617) 724-2764
MGH-led team finds gene for crippling neurologic disorder
Protein provides possible clue to disease triggers
BOSTON -- A research team led by investigators from the
Massachusetts General Hospital (MGH) has identified and cloned
the gene responsible for early-onset dystonia, a crippling,
inherited neurological disorder that begins in childhood. The
discovery, announced in the September issue of Nature Genetics,
is the culmination of more than 15 years of work and contains
important clues that could lead to better understanding of the
disease and possible preventive treatments.
There are many types of dystonia, a term that generally refers to
sustained, involuntary muscle contractions that can twist and
contort parts of the body. Early-onset dystonia, usually
appearing before the age of 11, is the most common and severe
hereditary form of the disorder, affecting about 50,000 people in
North America. Symptoms usually begin in the legs or arms and
spread to the rest of the body, causing it to twist into
unnatural postures; symptoms worsen when patients are fatigued or
stressed. Patients with advanced dystonia may be confined to a
wheelchair or bedridden. The lifelong condition is more
prevalent than Huntington's disease or amyotrophic lateral
sclerosis (ALS or Lou Gehrig's disease) among the general
population and has a higher frequency among Ashkenazi Jews, those
of Eastern European ancestry.
"We look on dystonia as a 'stealth crippler'," says Xandra O.
Breakefield, PhD, of the MGH Molecular Neurogenetics Unit, leader
of the research team. "In contrast to other movement disorders,
like Parkinson's disease, there is no visible evidence of damage
to the brain and no truly effective drug treatment. Only after
identifying the responsible gene and then determining the
function of its protein can we understand exactly how this
disease produces its symptoms." Along with scientists from
Breakefield's MGH lab, the paper's coauthors include researchers
from the Columbia University College of Physicians and Surgeons
and Mount Sinai School of Medicine in New York, Oregon Health
Sciences University in Portland, Stanford University in
California and the Howard Hughes Medical Institute at the MGH.
In the Nature Genetics paper, first author Laurie Ozelius, PhD,
and her collaborators describe their pinpointing the location of
the gene, called DYT1, on chromosome 9 and their discovery that
virtually all cases of early-onset dystonia are attributed to the
same mutation -- the deletion of three "letters" in the genetic
code that spells out the sequence of amino acids in a protein.
In other genetic diseases different mutations in the same gene
are usually found in different families.
"This situation, with only one mutation being associated with
disease, is unique," Ozelius says. "It suggests that this
specific area of the gene and of the protein it codes for must be
crucial to its function, which is still unknown."
The researchers also found that the DYT1 protein has significant
similarities to the heat-shock proteins and proteases. Found in
virtually all living organisms, the heat-shock proteins/proteases
help cells recover from stresses including heat, traumatic injury
and chemical poisoning. Until now, no human disease has been
associated with these proteins.
"This is quite exciting, because it may help us understand how
stress situations bring on a variety of neurological diseases,
including this one," says Breakefield. She explains that only 30
percent of those inheriting the DYT1 gene mutation actually
develop dystonia and that vulnerability to the disease seems to
disappear after age 28. "The disease needs a trigger -- perhaps
an environmental stress, infection or a change in another gene.
If the mutated gene product is set off, there is no stopping it,
but if the process does not start by 28, people with the mutation
are virtually free from the risk of developing symptoms. We now
have an important clue to help us find that trigger and, we hope,
to stop it."
The members of this research team have been searching for the
DYT1 gene since the early 1980s, when many of them worked
together at Yale University. In 1989, they discovered the first
marker for the gene, which localized it to a segment of
chromosome 9. While the MGH researchers worked out the genetic
and molecular aspects of this discovery, their work relies on
crucial contributions from their collaborators. Susan Bressman,
MD, Stanley Fahn, MD, and members of the Dystonia Clinical
Research Center at Columbia Presbyterian Medical Center --
including Mitchell Brin, MD, now at Mount Sinai -- provided blood
and DNA samples from dystonia patients and their family members.
Patricia Kramer, PhD, at Oregon and Neil Risch, PhD, at Stanford,
provided key statistical information tracing patterns of the
gene's inheritance, including its prevalence among Ashkenazi
Jews. A collaboration between Risch and the Columbia group
confirmed that the gene mutation was dominant -- requiring
inheritance from only a single parent -- and disproved the
previous theory that it was recessive and had to be inherited
from both parents.
One of the most immediate applications of this discovery will be
the availability of a simple, inexpensive blood test to confirm
whether children with dystonia symptoms have this disorder rather
than other diseases -- like cerebral palsy or early-onset
Parkinson's disease -- that can appear similar. If future
research discovers the triggers that set off dystonia in
vulnerable individuals, identifying these carriers of the
mutation could allow application of preventive treatments.
Supporters of this research include the Dystonia Medical Research
Foundation, the National Institute of Neurological Disorders and
Stroke, the Jack Fasciana Fund for the Support of Dystonia
Research, the Histadrut Foundation and the Bachmann-Strauss
Dystonia and Parkinson Foundation at Mount Sinai.
# # #
Additional contacts:
Dystonia Medical Research Foundation
Rosie Presti (312) 755-0198
National Institute of Neurological Disorders and Stroke
Marcia Vital, Public Affairs (301) 496-5751
Jack Fasciana Fund for the Support of Dystonia Research
John Fasciana (212) 922-5300
Bachmann-Strauss Dystonia and Parkinson Foundation
Bonnie Strauss (212) 241-5614
Columbia University College of Physicians and Surgeons (Drs.
Bressman and Fahn)
Carolyn Conway, Public Affairs (212) 305-3900
Mount Sinai School of Medicine (Dr. Brin)
Mel Granick, Public Affairs (212) 241-9300
Oregon Health Sciences University (Dr. Kramer)
Julie Remington, Public Affairs (503) 494-4156
Stanford University (Dr. Risch)
Rosanne Spector, Public Affairs (650) 725-5374
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