Sep. 6, 1997 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 wheel-chair 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.
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