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Gene Sequenced for Disabling Childhood Movement Disorder: Early-Onset Torsion Dystonia Protein Found

For release: Wednesday, September 3, 1997

Scientists have sequenced the gene responsible for early-onset torsion dystonia and have found a new class of proteins that may provide insight into all of the dystonia disorders. Dystonia disorders cause involuntary movements and prolonged muscle contraction, resulting in twisting body motions, tremor, and abnormal posture. The discovery of the gene will make diagnosis of early-onset torsion dystonia easier and allow scientists to investigate other factors that might contribute to the disease. The study, supported by the National Institute of Neurological Disorders and Stroke (NINDS), is published in the September 1997 issue of Nature Genetics.*

"The cloning of this gene is a long sought-after goal," says Zach W. Hall, Ph.D., Director of the NINDS. "Its discovery is a signal achievement which will help us understand the pathological basis of dystonia and other movement disorders."

NINDS grantees, Xandra O. Breakefield, Ph.D., and Laurie J. Ozelius, Ph.D., neurogeneticists at Massachusetts General Hospital (MGH) in Boston and lead authors of the study, have been searching for the dystonia gene for more than 15 years. Their team included investigators at Columbia Presbyterian Medical Center and Mt. Sinai Hospital in New York City, Stanford University in Stanford, California, and Oregon Health Sciences University in Portland, Oregon. In 1989 the team localized or mapped 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. Ozelius. "But, of course, this is just the first step, and we hope we can come up with some treatments for the patients."

"TorsinA is a protein we've never seen before," says Dr. Breakefield, "but we already have clues about its function because it resembles a class of proteins that protects cells from stress and trauma."

Once they sequenced the DYT1 gene, the investigators compared it to other genes from a large database of genetic information. The DYT1 gene resembled genes that code for proteins responsible for binding adenosine triphosphate (ATP), the energy-containing molecules of cells. TorsinA and related ATP-binding proteins resemble a class of proteins called heat-shock proteins.

Heat-shock proteins act as thermoregulators to other proteins involved in cellular function and metabolism. They protect proteins from temperature fluctuations and help proteins maintain their shape. By maintaining the strength and resiliency of cellular proteins, heat-shock proteins protect cells from deadly environmental, biological, and chemical stress.

In patients with early-onset torsion dystonia, the DYT1 gene has a mutation that results in the loss of an amino acid, glutamic acid, in the torsinA protein. Somehow, this defective protein disrupts communication among the neurons responsible for movement and muscle control, leading to the symptoms of the dystonia disorder.

"Perhaps the mutated torsinA protein blocks the normal protective mechanisms for cells under stress," says Dr. Breakefield. "If so, this disorder would provide incredible insight into the role that environmental factors play in triggering symptoms in humans with a genetic predisposition to neurologic and psychiatric diseases."

Dystonia appears when a person has one copy of the mutated gene and one copy of the normal gene. Although this means that the disease is dominant, because only one copy of the mutated gene is needed to cause it, only 30 to 40 percent of people who have a mutated gene develop symptoms. Geneticists call this phenomenon "penetrance." Scientists believe that there must be other factors, environmental stresses or interacting genes, that influence the expression of the mutated gene and cause the disorder.

"We know that people carrying the mutated gene are vulnerable only within a certain age range, between the ages of 5 and 28," says Giovanna Spinella, M.D., a pediatric neurologist at the NINDS. "Once gene carriers pass this age range, it's very unlikely that they will develop the disorder. This means there must be some environmental or biological factors influencing the expression of the gene around this time of life."

Symptoms of early-onset torsion dystonia, also called idiopathic or generalized torsion dystonia, usually surface in childhood around the age of 12. Symptoms typically start in one part of the body, usually in an arm or leg, and eventually spread to the rest of the body within about 5 years. Early-onset torsion dystonia is not fatal, but it can be severely debilitating. Most children with the disorder are unable to perform the simplest of motor tasks and are confined to a wheelchair by the time they reach adulthood.

Dystonia disorders affect about 30 people out of 100,000. The prevalence of early-onset torsion dystonia varies depending upon the population. Ashkenazi Jews have a high prevalence of the disorder, around 1 in 10,000, due to a mutation in the DYT1 gene in a common ancestor hundreds of years ago. That mutation, called a founder mutation, has been passed down from the original carrier of the gene to subsequent generations. Dr. Breakefield's team believes that the same mutation in the DYT1 gene appeared independently in several other ethnic populations throughout history, and is possibly one of only a few mutations that result in early-onset torsion dystonia.

Researchers believe that dystonia may be caused by a breakdown of the dopamine system in the basal ganglia, a collection of structures in the brain that control movement. Dopamine is a neurotransmitter that regulates neuronal communication within the basal ganglia. A malfunctioning dopamine system in the basal ganglia is responsible for many movement disorders, including Parkinson's disease. Researchers have mapped a total of seven genes causing dystonia and sequenced two that code for proteins involved in dopamine systems. Dopamine therapy seems to work for some kinds of dystonia, but is not effective for children with generalized torsion dystonia.

The next task for Drs. Breakefield and Ozelius is to clarify the function of torsinA. Working in collaboration with other members of the team they will develop an animal model for early-onset torsion dystonia. An animal model could provide valuable insights into the environmental factors that influence the onset of the disorder. Once researchers identify these environmental stresses, they may be able to develop interventional therapies to prevent the mutated gene from causing the disorder.

In addition to the NINDS, this study was also funded by the Dystonia Medical Research Foundation, the Jack Fasciana Fund for the Support of Dystonia Research, and the Bachmann-Strauss Dystonia and Parkinson Foundation, Inc.

The NINDS, one of the National Institutes of Health located in Bethesda, Maryland, 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.

*Ozelius, L. J.; Bressman, S. B.; Brin, M. F.; Buckler, A. J.; Corey, D. P.; Fahn, S.; Gusella, J. F.; Hewett, J. W.; Kramer, P. L.; de Leon, D.; Page, C. E.; Raymond, D.; Risch, N. J.; Shalish, C.; and Breakefield, X. O. "The; early onset torsion dystonia gene (DYT1) encodes an ATP-binding protein." Nature Genetics, Vol. 17; September, 1997; pp. 40-48.

Originally prepared by Marcia Vital, NINDS Office of Communication and Public Liaison.

Last Modified August 7, 2009