A rare sequence variant in intron 1 of THAP1 is associated with primary dystonia.

• Type of Material: Article
• Authors: Satya R. Vemula, University of Tennessee Health Science Center; Jianfeng Xiao, University of Tennessee Health Science Center; Yu Zhao, University of Tennessee Health Science Center; Robert W. Bastian, Bastian Voice Institute; Joel S. Perlmutter, Washington University School of Medicine; Brad A. Racette, Washington University School of Medicine; Randal C. Paniello, Washington University School of Medicine; Zbigniew K. Wszolek, Mayo Clinic; Ryan J. Uitti, Mayo Clinic; Jay A. Van Gerpen, Mayo Clinic; Peter Hedera, Vanderbilt University; Daniel D. Truong, Parkinson's & Movement Disorder Institute; Andrew Blitzer, New York Center for Voice and Swallowing Disorders; Monika Rudzińska, Jagiellonian University Medical College in Krakow; Dragana Momčilović, Medical Faculty University of Belgrade; Hyder Jinnah, Emory University; Karen Frei, Loma Linda University Health System; Ronald F. Pfeiffer, University of Tennessee Health Science Center; Mark S. LeDoux, University of Tennessee Health Science Center
• Language: English
• Date: 2014-05
• Publisher: Wiley Open Access
• Publication Version: Final Published Version
• Copyright Statement: © 2014 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc. This
• License: Creative Commons Attribution 3.0 Unported
• Final Published Version (URL): http://dx.doi.org/10.1002/mgg3.67
• Title of Journal or Parent Work: Molecular Genetics and Genomic Medicine
• ISSN: 2324-9269
• Volume: 2
• Issue: 3
• Start Page: 261
• End Page: 272
• Grant/Funding Information: At the Parkinson's & Movement Disorder Institute, work was supported by the Long Beach Memorial Foundation, Orange Coast Memorial Foundation, and the Parkinson's & Movement Disorder Foundation.; The Dystonia Coalition is part of the NIH Rare Diseases Clinical research Network.; At Mayo Clinic Jacksonville, work was supported by the NIH National Institute of Neurological Disease and Stroke Morris K. Udall Center of Excellence for Parkinson Disease Research grant (P50-NS072187) to Z. K. W., J. V. G., and R. J. U., Mayo Clinic Center for Regenerative Medicine (Z. K. W.), and a gift from Carl Edward Bolch, Jr. and Susan Bass Bolch (Z. K. W.).; At Washington University School of Medicine, work was supported by the NIH National Institute of Neurological Disease and Stroke grants P30NS05710 (Neuroscience Blueprint Grant) and Clinical Sciences Translation Award UL1 TR000448, the American Parkinson's Disease Association (APDA) Advanced Research Center, the Greater St. Louis Chapter of the APDA, the Barnes-Jewish Hospital Foundation (PD Research Fund and the Elliot H. Stein Family Fund), the Missouri Chapter of the Dystonia Research Foundation and the Murphy Fund.; This study was supported by the Neuroscience Institute at the University of Tennessee Health Science Center (M. S. L.), Dystonia Medical Research Foundation (M. S. L. and Z. K. W.), National Institutes of Health (NIH) National Institute of Neurological Disease and Stroke grant R01NS069936 (M. S. L.) and NIH U54 Dystonia Coalition (1U54NS065701) Pilot Projects Program (M. S. L.).; Funding and/or programmatic support for this project has been provided by NS067501 from the NIH Office of Rare Diseases Research and the National Institute of Neurological Disorders and Stroke.
• Keywords: Dystonia; DYT6; intronic variant; minigene assay; THAP1
• Research Categories: Biology, Neuroscience; Biology, General; Biology, Genetics

Abstract

Although coding variants in THAP1 have been causally associated with primary dystonia, the contribution of noncoding variants remains uncertain. Herein, we examine a previously identified Intron 1 variant (c.71+9C>A, rs200209986). Among 1672 subjects with mainly adult-onset primary dystonia, 12 harbored the variant in contrast to 1/1574 controls (P < 0.01). Dystonia classification included cervical dystonia (N = 3), laryngeal dystonia (adductor subtype, N = 3), jaw-opening oromandibular dystonia (N = 1), blepharospasm (N = 2), and unclassified (N = 3). Age of dystonia onset ranged from 25 to 69 years (mean = 54 years). In comparison to controls with no identified THAP1 sequence variants, the c.71+9C>A variant was associated with an elevated ratio of Isoform 1 (NM_018105) to Isoform 2 (NM_199003) in leukocytes. In silico and minigene analyses indicated that c.71+9C>A alters THAP1 splicing. Lymphoblastoid cells harboring the c.71+9C>A variant showed extensive apoptosis with relatively fewer cells in the G2 phase of the cell cycle. Differentially expressed genes from lymphoblastoid cells revealed that the c.71+9C>A variant exerts effects on DNA synthesis, cell growth and proliferation, cell survival, and cytotoxicity. In aggregate, these data indicate that THAP1 c.71+9C>A is a risk factor for adult-onset primary dystonia.