Journal
NEUROLOGY
Volume 74, Issue 3, Pages 229-238Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1212/WNL.0b013e3181ca00ca
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Funding
- Medtronic Inc
- NIH [1R01 NS41509, R01 NS050425, R01 NS058714, P30 NS057105, 5R01 NS037167-10, U10 NS44455, R01HG02449, R01 ES01374301A2, P42 ES04696, K24 NS060825, R21 ES017504, K23 NS43351, RO1 NS050425, 1R01NS41509, RO1 NS058714, P01AG017216-1, R01AG015866-1, P50NS 40256, CIHR P 121849]
- NIH/NCRR [RR024992, R01ES013743, R01 NS039821, R01NS058797, RO1 HD056015, U54 NS065701]
- Huntington Disease Society of American Center of Excellence
- Michael J. Fox Foundation
- HiQ Foundation
- McDonnell Center for Higher Brain Function
- Greater St. Louis Chapter of the American Parkinson Disease Association
- Bander Foundation for Medical Ethics and Advanced PD Research Center at Washington University
- BJH Foundation
- BJHF/ICTS
- Mayo Clinic Florida
- PARF [C06-01]
- Novartis
- Eisai Inc.
- Advanced Neuromodulations Systems
- NIH/NINDS [P50NS 40256, 1R01NS058988, U10 NS44482, R01 NS037167, 1R03NS053840, R01NS048458, 5U01 NS052592]
- Michael J. Fox
- National Parkinson Foundation
- Allergan
- Boehringer Ingelheim
- Valeant
- Teva Neurosciences
- Schwarz
- Solvay
- Neurogen
- Ipsen
- Teva
- UCB Pharma Merz
- Schering Plough
- Acadia
- Merz Pharma
- Revance Therapeutics
- Dystonia Medical Research Foundation
- Bachmann-Strauss Dystonia & Parkinson Foundation
- Xenoport
- HP Therapeutics Foundation
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Background: THAP1 encodes a transcription factor (THAP1) that harbors an atypical zinc finger domain and regulates cell proliferation. An exon 2 insertion/deletion frameshift mutation in THAP1 is responsible for DYT6 dystonia in Amish-Mennonites. Subsequent screening efforts in familial, mainly early-onset, primary dystonia identified additional THAP1 sequence variants in non-Amish subjects. Objective: To examine a large cohort of subjects with mainly adult-onset primary dystonia for sequence variants in THAP1. Methods: With high-resolution melting, all 3 THAP1 exons were screened for sequence variants in 1,114 subjects with mainly adult-onset primary dystonia, 96 with unclassified dystonia, and 600 controls (400 neurologically normal and 200 with Parkinson disease). In addition, all 3 THAP1 exons were sequenced in 200 subjects with dystonia and 200 neurologically normal controls. Results: Nine unique melting curves were found in 19 subjects from 16 families with primary dystonia and 1 control. Age at dystonia onset ranged from 8 to 69 years (mean 48 years). Sequencing identified 6 novel missense mutations in conserved regions of THAP1 (G9C [cervical, masticatory, arm], D17G [cervical], F132S [laryngeal], I149T [cervical and generalized], A166T [laryngeal], and Q187K [cervical]). One subject with blepharospasm and another with laryngeal dystonia harbored a c.-42C>T variant. A c.57C>T silent variant was found in 1 subject with segmental craniocervical dystonia. An intron 1 variant (c.71 + 9C>A) was present in 7 subjects with dystonia (7/1,210) but only 1 control (1/600). Conclusions: A heterogeneous collection of THAP1 sequence variants is associated with varied anatomical distributions and onset ages of both familial and sporadic primary dystonia. Neurology (R) 2010; 74: 229-238
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