Dystonia has been defined as a syndrome of sustained muscle contractions, frequently causing twisting and repetitive movements, or abnormal postures. Recently, a mutation in the gene THAP1 was identified as the cause of DTY6 dystonia in Amish-Mennonites. Follow-up high-throughput screening of patients with sporadic and familial, mainly adult-onset, primary dystonia showed that a diverse assortment of THAP1 sequence variants is associated with varied anatomical patterns and onset ages of primary dystonia in diverse populations. Clearly, THAP1 appears to be the most important genetic etiology for adult-onset primary dystonia identified to date. THAP1 encodes the transcription factor THAP1. Using a large biorepository containing DNA and lymphocytes from subjects with adult-onset primary dystonia, we will examine associations between dystonia risk and recently identified THAP1 sequence variants, and interrogate THAP1 for copy number and additional coding and non-coding sequence variants. Using lymphoblastoid cell lines, transfected cell lines and gene expression profiling, we will determine the effects of individual THAP1 sequence variants on THAP1 expression and function. This work will have immediate clinical ramifications in the context of genetic testing and counseling. Recent studies in humans and animal models strongly suggest that DYT1, DYT6 and other forms of dystonia may be neurodevelopmental disorders. Transcriptional dysregulation and abnormal cerebellar output have been other major themes in dystonia research. Accordingly, we will examine the developmental expression of THAP1 protein and transcript in neural tissues and generate a model of DYT6 dystonia by knocking-out the Thap1 gene in mice. Preliminary data indicates that THAP1 is expressed at high levels in developing Purkinje cells. Morphological studies in Thap1-KO mice will allow us to test the hypothesis that THAP1 is essential for the normal morphological development of cerebellar Purkinje cells. In addition, data from ChIP-Seq and ChIP-chip experiments will be merged in order to identify THAP1 DNA binding sites in vivo during the maturation of cerebellar cortex. Completion of these experiments will unveil dystonia-associated cellular networks, point out candidate genes for primary dystonia and define molecular targets for the treatment of dystonia.

Public Health Relevance

Dystonia is a common disorder of the nervous system that manifests as prolonged muscle contractions leading to abnormal postures of the face, neck, trunk and limbs. Mutations in the THAP1 gene cause dystonia in children and adults. Our research will attempt to determine exactly how THAP1 mutations lead to the development of dystonia.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS069936-03
Application #
8318287
Study Section
Clinical Neuroscience and Neurodegeneration Study Section (CNN)
Program Officer
Sieber, Beth-Anne
Project Start
2010-08-20
Project End
2014-07-31
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
3
Fiscal Year
2012
Total Cost
$317,275
Indirect Cost
$102,900
Name
University of Tennessee Health Science Center
Department
Neurology
Type
Schools of Medicine
DUNS #
941884009
City
Memphis
State
TN
Country
United States
Zip Code
38163
Xiao, Jianfeng; Vemula, Satya R; Xue, Yi et al. (2016) Motor phenotypes and molecular networks associated with germline deficiency of Ciz1. Exp Neurol 283:110-20
LeDoux, Mark S; Vemula, Satya R; Xiao, Jianfeng et al. (2016) Clinical and genetic features of cervical dystonia in a large multicenter cohort. Neurol Genet 2:e69
Xiao, Jianfeng; Vemula, Satya R; Xue, Yi et al. (2016) Role of major and brain-specific Sgce isoforms in the pathogenesis of myoclonus-dystonia syndrome. Neurobiol Dis 98:52-65
Shakkottai, Vikram G; Batla, Amit; Bhatia, Kailash et al. (2016) Current Opinions and Areas of Consensus on the Role of the Cerebellum in Dystonia. Cerebellum :
Xiao, Jianfeng; Thompson, Misty M; Vemula, Satya R et al. (2016) Blepharospasm in a multiplex African-American pedigree. J Neurol Sci 362:299-303
Xiao, Jianfeng; Vemula, Satya R; LeDoux, Mark S (2014) Recent advances in the genetics of dystonia. Curr Neurol Neurosci Rep 14:462
Theuns, Jessie; Verstraeten, Aline; Sleegers, Kristel et al. (2014) Global investigation and meta-analysis of the C9orf72 (G4C2)n repeat in Parkinson disease. Neurology 83:1906-13
Luciano, Angelo Y; Jinnah, H A; Pfeiffer, Ronald F et al. (2014) Treatment of myoclonus-dystonia syndrome with tetrabenazine. Parkinsonism Relat Disord 20:1423-6
Vemula, Satya R; Xiao, Jianfeng; Bastian, Robert W et al. (2014) Pathogenic variants in TUBB4A are not found in primary dystonia. Neurology 82:1227-30
Vemula, Satya R; Xiao, Jianfeng; Zhao, Yu et al. (2014) A rare sequence variant in intron 1 of THAP1 is associated with primary dystonia. Mol Genet Genomic Med 2:261-72

Showing the most recent 10 out of 31 publications