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

Satya R. Vemula, Departments of Neurology and Anatomy & Neurobiology, University of Tennessee Health Science Center Memphis, Tennessee, 38163.
Jianfeng Xiao, Departments of Neurology and Anatomy & Neurobiology, University of Tennessee Health Science Center Memphis, Tennessee, 38163.
Yu Zhao, Departments of Neurology and Anatomy & Neurobiology, University of Tennessee Health Science Center Memphis, Tennessee, 38163.
Robert W. Bastian, Bastian Voice Institute Downers Grove, Illinois.
Joel S. Perlmutter, Department of Neurology, Washington University School of Medicine St. Louis, Missouri.
Brad A. Racette, Department of Neurology, Washington University School of Medicine St. Louis, Missouri.
Randal C. Paniello, Department of Otolaryngology-Head and Neck Surgery, Washington University School of Medicine St. Louis, Missouri.
Zbigniew K. Wszolek, Department of Neurology, Mayo Clinic Jacksonville, Florida, 32224.
Ryan J. Uitti, Department of Neurology, Mayo Clinic Jacksonville, Florida, 32224.
Jay A. Van Gerpen, Department of Neurology, Mayo Clinic Jacksonville, Florida, 32224.
Peter Hedera, Department of Neurology, Vanderbilt University Nashville, Tennessee.
Daniel D. Truong, Parkinson's & Movement Disorder Institute Fountain Valley, California, 92708.
Andrew Blitzer, New York Center for Voice and Swallowing Disorders New York, New York.
Monika Rudzińska, Department of Neurology, Jagiellonian University Medical College in Krakow Kraków, Poland.
Dragana Momčilović, Clinic for Child Neurology and Psychiatry, Medical Faculty University of Belgrade Belgrade, Serbia.
Hyder A. Jinnah, Departments of Neurology, Human Genetics, and Pediatrics, School of Medicine, Emory University Atlanta, Georgia, 30322.
Karen Frei, Department of Neurology, Loma Linda University Health System Loma Linda, California, 92354.
Ronald F. Pfeiffer, Departments of Neurology and Anatomy & Neurobiology, University of Tennessee Health Science Center Memphis, Tennessee, 38163.
Mark S. LeDoux, Departments of Neurology and Anatomy & Neurobiology, University of Tennessee Health Science Center Memphis, Tennessee, 38163.

Document Type

Article

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.

Publication Date

5-1-2014

Publication Title

Molecular genetics & genomic medicine

ISSN

2324-9269

Volume

2

Issue

3

First Page

261

Last Page

72

PubMed ID

24936516

Digital Object Identifier (DOI)

10.1002/mgg3.67

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