Primary torsion dystonias (PTDs) are a group of movement disorders characterized by twisting muscle contractures, where dystonia is the only clinical sign (except for tremor) and there is no evidence of neuronal degeneration or an acquired cause. Seven genes have been mapped for primary dystonia including DYT1, 2, 4, 6, 7, 13 and 17, however until recently, the genetic basis for only one of these, DYT1, responsible for most cases of early onset generalized dystonia, has been identified and is caused by a heterozygous three basepair in-frame deletion in the TOR1A gene. This mutation accounts for about 90% of early onset PTD cases in the Ashkenazi Jewish population due to a founder effect but in the non-Jewish population it accounts for less than 50%. We have recently identified a new early onset PTD gene, THAP1, mutations in which cause DYT6 dystonia. In this application, we will generate overexpressing transgenic mice harboring the human THAP1 wt or mutant protein and will generate a Thap1 neuronal specific conditional knock-out mouse. We will study these mice to determine the normal function of the THAP1 gene product and whether the disease is caused by a gain or loss of function mechanism. All mice generated in this project will be evaluated for neurologic and motoric phenotypes and undergo neurochemical and neuropathological analyses. Development of mouse models specific for DYT6 dystonia will allow for the determination of common mechanisms among early onset PTDs and provide the foundation for devising novel treatments for these poorly understood and disabling diseases.

Public Health Relevance

The genetic basis of most Primary torsin dystonias (PTD) remains unknown and the pathophysiological mechanisms are poorly understood. Treatment is incomplete and empiric. With the discovery of a new PTD gene we can now generate mouse models specific to this disorder. Development of these models will provide a unique tool to clarify the underlying mechanisms of dystonia and provide the foundation for devising novel treatments for these poorly understood and disabling diseases.

Agency
National Institute of Health (NIH)
Institute
National Center for Research Resources (NCRR)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21RR026123-02
Application #
8037041
Study Section
Cell Death in Neurodegeneration Study Section (CDIN)
Program Officer
O'Neill, Raymond R
Project Start
2010-03-01
Project End
2012-02-29
Budget Start
2011-03-01
Budget End
2012-02-29
Support Year
2
Fiscal Year
2011
Total Cost
$293,659
Indirect Cost
Name
Icahn School of Medicine at Mount Sinai
Department
Genetics
Type
Schools of Medicine
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029
Ruiz, Marta; Perez-Garcia, Georgina; Ortiz-Virumbrales, Maitane et al. (2015) Abnormalities of motor function, transcription and cerebellar structure in mouse models of THAP1 dystonia. Hum Mol Genet 24:7159-70
Brashear, Allison; Cook, Jared F; Hill, Deborah F et al. (2012) Psychiatric disorders in rapid-onset dystonia-parkinsonism. Neurology 79:1168-73
Barbano, Richard L; Hill, Deborah F; Snively, Beverly M et al. (2012) New triggers and non-motor findings in a family with rapid-onset dystonia-parkinsonism. Parkinsonism Relat Disord 18:737-41
Sengel, Cem; Gavarini, Sophie; Sharma, Nutan et al. (2011) Dimerization of the DYT6 dystonia protein, THAP1, requires residues within the coiled-coil domain. J Neurochem 118:1087-100
Sharma, Nutan; Armata, Ioanna A; Multhaupt-Buell, Trisha J et al. (2011) Mutation in 5' upstream region of GCHI gene causes familial dopa-responsive dystonia. Mov Disord 26:2140-1
Fuchs, Tania; Ozelius, Laurie J (2011) Genetics of dystonia. Semin Neurol 31:441-8
Shanker, Vicki; Groves, Mark; Heiman, Gary et al. (2011) Mood and cognition in leucine-rich repeat kinase 2 G2019S Parkinson's disease. Mov Disord 26:1875-80