Mount Sinai Scientists Discover New Genetic Basis for Dystonia, a Debilitating Movement Disorder Impacting 500,000 North Americans

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Discovery of New Gene Provides Opportunity for Development of New Drugs and Prenatal Screening for Dystonia

Researchers from the Icahn School of Medicine at Mount Sinai, in collaboration with researchers from other institutions, have identified a causative gene for primary torsion dystonia (PTD), a debilitating movement disorder that impacts an estimated 500,000 people in North America alone.

The findings, published online December 9 in Nature Genetics, provide novel insights into the genetic basis underlying PTD. The research study was led by Laurie Ozelius, PhD, Associate Professor in the Department of Genetics and Genomic Sciences at the Icahn School of Medicine at Mount Sinai. The discovery identifies the human G α olf (GNAL) gene, the first PTD gene that directly points to the dopamine signal transduction system as the origin of pathophysiology. Exome sequencing of patients in two families with dystonia revealed mutations in GNAL. Further screening of 39 other families with a history of PTD identified another six mutations in this gene. The research provides the potential opportunity for developing new treatments, and prenatal screening tests.

Dystonia is a movement disorder characterized by repetitive twisting muscle contractions and postures that can affect the face, neck, arms, legs, or torso. Common symptoms include tremors, voice problems, or a dragging foot. The molecular pathophysiology of the disease is poorly understood, in part due to limited knowledge of the genetic basis of the disorder. The disease is most often inherited in an autosomal-dominant manner, with reduced penetrance ranging between 15-60 percent for different forms of PTD. With more than nine loci mapped for PTD, only three genes have been previously identified.

“The successful application of exome sequencing for the identification of the GNAL gene proves that this is a powerful and efficient tool which will rapidly accelerate the pace of dystonia gene discovery and consequently, our understanding of the pathways involved in PTD,” said Laurie Ozelius, PhD, Associate Professor in the Department of Genetics and Genomic Sciences at the Icahn School of Medicine at Mount Sinai. “Any new gene offers the potential to develop new therapeutics, but because GNAL belongs to a well-studied signal transduction pathway, other components in this pathway may also be targets for drug development,” said Tania Fuchs, PhD, Instructor in the Department of Genetics and Genomic Sciences at the Icahn School of Medicine at Mount Sinai, who is first author of the paper.

This research was funded in part by the Dystonia Medical Research Foundation, the Bachmann-Strauss Dystonia & Parkinson Foundation, and the National Institute of Health (NIH).

Art Kessler, President of the Dystonia Medical Research Foundation, said, “We are delighted that we were able to support this research into the underlying genetic basis of dystonia. While not widely known, dystonia affects more people than muscular dystrophy, Huntington's disease and Lou Gehrig's disease combined. I’ve lived with primary torsion dystonia since childhood, so this discovery hits very close to home for my family and for so many others in the community.”

Bonnie Strauss, President and Founder of the Bachmann-Strauss Dystonia & Parkinson Foundation commented, “There is no definitive test or diagnosis for dystonia, nor is there a known cure. While hundreds of thousands of adults and children suffer from symptoms related to the disease, a large majority of patients never receive a proper prognosis. This exciting new research may provide an opportunity for a definitive genetic test to aid diagnosis and treatment.”

Study authors include scientists from Beth Israel Medical Center; Albert Einstein College of Medicine; Scripps Research Institute; University of California, San Francisco; Emory University School of Medicine; Toronto Western Hospital; Jefferson Hospital for Neuroscience; Massachusetts General Hospital, and Institute National de la Santé et la Recherche Médicale (INSERM).

About The Mount Sinai Medical Center

The Mount Sinai Medical Center encompasses both The Mount Sinai Hospital and the Icahn School of Medicine at Mount Sinai. Established in 1968, Icahn School of Medicine is one of the leading medical schools in the United States, and is noted for innovation in education, biomedical research, clinical care delivery, and local and global community service. It has more than 3,400 faculty in 32 departments and 14 research institutes, and ranks among the top 20 medical schools both in National Institutes of Health (NIH) funding and by U.S. News & World Report.

The Mount Sinai Hospital, founded in 1852, is a 1,171-bed tertiary- and quaternary-care teaching facility and one of the nation’s oldest, largest and most-respected voluntary hospitals. In 2012, U.S. News & World Report ranked The Mount Sinai Hospital 14th on its elite Honor Roll of the nation’s top hospitals based on reputation, safety, and other patient-care factors. Of the top 20 hospitals in the United States, Mount Sinai is one of 12 integrated academic medical centers whose medical school ranks among the top 20 in NIH funding and by U.S. News & World Report and whose hospital is on the U.S. News & World Report Honor Roll. Nearly 60,000 people were treated at Mount Sinai as inpatients last year, and approximately 560,000 outpatient visits took place.

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