| Torsion Dystonia Gene
By Sean Henahan, Access Excellence
 Boston,
MA (9/5/97)- A fifteen year search has yielded a long sought gene for
a movement disorder called torsion dystonia. The discovery will allow early
diagnosis of this crippling disease and could also contribute to understanding
of a wide variety of movement disorders.
"The cloning of this gene is a long sought-after goal," says Zach W.
Hall, Ph.D., Director of the National Institute of Neurological Disorders
and Stroke. "Its discovery is a signal achievement which will help us
understand the pathological basis of dystonia and other movement disorders."
Dystonias are disorders characterized by 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. Patients with advanced dystonia may be confined to a wheel-chair
or bedridden. The disease is more common lifelong condition is more common
than the better known crippling diseases, Huntington's disease and
amyotrophic lateral sclerosis (ALS or Lou Gehrig's disease). The incdience
is especially high among Ashkenazi Jews, those of Eastern European ancestry.
"We look on dystonia as a 'stealth crippler'," says Xandra O. Breakefield,
PhD, of the Massachusetts General Hospital 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."
Colllaborators across the US have been looking for the gene for 15 years.
Important progress came in 1989 when the team localized the gene to chromosome
9 and named it DYT1. Now, they have sequenced the DYT1 gene and found that
it codes for a previously unknown protein which the team named "torsinA."
"The most exciting aspect to me is that we found it. We found the gene!"
says Dr. Laurie J. Ozelius, Ph.D., "But, of course, this is just the first
step, and we hope we can come up with some treatments for the patients."
In addition to locating the gene, the researchers report that the same
three-base mutation appears to be responsible for virtually all cases of
early-onset dystonia 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."
Another interesting observation was that the DYT1 protein was similar
in structure to the
heat-shock proteins and proteases. Heat-shock proteins and proteases
help cells recover from stresses including heat, traumatic injury and chemical
poisoning. This is the first time a 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 researchers also confirmed that the gene mutation was dominant --
requiring inheritance from only a single parent. This disproved the prevailing
theory that the disease was recessive and had to be inherited from
both parents.
The new discovrey should soon produce 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. Future studies based on this discovery could
lead to identification of triggers of the disease and possibly even preventive
treatments.
The research appears in the September 1997 issue of Nature Genetics.
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