Primary torsion dystonias (PTD) are a group of movement disorders characterized by twisting muscle contractures, where dystonia is the only clinical sign and there is no evidence of neuronal degeneration or an acquired cause. There are eight PTD loci assigned (DYT1, 2, 4, 6, 7, 13, 17 and 21), but only two of the genes (TOR1A-DYT1 and THAP1-DYT6) have been isolated. Apparent locus heterogeneity, reduced penetrance and significant phenotypic overlap between different forms of PTD limit the success of positional cloning approaches for dystonia gene discovery. New second generation sequencing technologies combined with whole exome capture libraries have revolutionized our ability to identify disease-causing mutations. Exome sequencing is based on capturing all exons of an individual's genome and sequencing them to an average 30X depth of coverage. We propose to apply exome sequencing to discover causative mutations in four multi- generation dystonia families. We will identify coding changes shared by a group of affected individuals in each family. These changes will be further tested for co-segregation with the disease in the remaining family members. The identified genes will be confirmed by screening for additional mutations in a collection of phenotypically similar small PTD families. Finally, in order to define the phenotypic spectrum associated with mutations, each gene will be examined in a large cohort of singleton PTD cases. The proposed research will lead to the identification of novel PTD genes and pathogenic mutations thus providing a key to understanding the molecular pathophysiology of the disease and the foundation for devising new therapeutic interventions.

Public Health Relevance

PROJECT NARRATIVE To find genetic causes of primary dystonia, we will use an innovative, powerful technique to screen all genes in selected dystonia families to identify causative mutations. To assess the clinical features associated with mutations in these genes, we will test a large cohort of primary dystonia patients. This research will reveal new causative genes for primary dystonia, thus contributing to our understanding of disease mechanism and providing a basis for development of new therapies.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Exploratory/Developmental Grants (R21)
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Genetics of Health and Disease Study Section (GHD)
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Sieber, Beth-Anne
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Icahn School of Medicine at Mount Sinai
Schools of Medicine
New York
United States
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Saunders-Pullman, Rachel; Fuchs, Tania; San Luciano, Marta et al. (2014) Heterogeneity in primary dystonia: lessons from THAP1, GNAL, and TOR1A in Amish-Mennonites. Mov Disord 29:812-8
Fuchs, Tania; Ozelius, Laurie J (2013) Genetics in dystonia: an update. Curr Neurol Neurosci Rep 13:410