title: A rare sequence variant in intron 1 of THAP1 is associated with primary dystonia.
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.
authors.affiliation: Departments of Neurology and Anatomy & Neurobiology, University of Tennessee Health Science Center Memphis, Tennessee, 38163.
authors.forename: Satya R
authors.initials: SR
authors.lastname: Vemula
authors.affiliation: Departments of Neurology and Anatomy & Neurobiology, University of Tennessee Health Science Center Memphis, Tennessee, 38163.
authors.forename: Jianfeng
authors.initials: J
authors.lastname: Xiao
authors.affiliation: Departments of Neurology and Anatomy & Neurobiology, University of Tennessee Health Science Center Memphis, Tennessee, 38163.
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Bastian Voice Institute Downers Grove, Illinois.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Bastian
authors.affiliation: Department of Neurology, Washington University School of Medicine St. Louis, Missouri.
authors.forename: Joel S
authors.initials: JS
authors.lastname: Perlmutter
authors.affiliation: Department of Neurology, Washington University School of Medicine St. Louis, Missouri.
authors.forename: Brad A
authors.initials: BA
authors.lastname: Racette
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, Washington University School of Medicine St. Louis, Missouri.
authors.forename: Randal C
authors.initials: RC
authors.lastname: Paniello
authors.affiliation: Department of Neurology, Mayo Clinic Jacksonville, Florida, 32224.
authors.forename: Zbigniew K
authors.initials: ZK
authors.lastname: Wszolek
authors.affiliation: Department of Neurology, Mayo Clinic Jacksonville, Florida, 32224.
authors.forename: Ryan J
authors.initials: RJ
authors.lastname: Uitti
authors.affiliation: Department of Neurology, Mayo Clinic Jacksonville, Florida, 32224.
authors.forename: Jay A
authors.initials: JA
authors.lastname: Van Gerpen
authors.affiliation: Department of Neurology, Vanderbilt University Nashville, Tennessee.
authors.forename: Peter
authors.initials: P
authors.lastname: Hedera
authors.affiliation: Parkinson's & Movement Disorder Institute Fountain Valley, California, 92708.
authors.forename: Daniel D
authors.initials: DD
authors.lastname: Truong
authors.affiliation: New York Center for Voice and Swallowing Disorders New York, New York.
authors.forename: Andrew
authors.initials: A
authors.lastname: Blitzer
authors.affiliation: Department of Neurology, Jagiellonian University Medical College in Krakow Kraków, Poland.
authors.forename: Monika
authors.initials: M
authors.lastname: Rudzińska
authors.affiliation: Clinic for Child Neurology and Psychiatry, Medical Faculty University of Belgrade Belgrade, Serbia.
authors.forename: Dragana
authors.initials: D
authors.lastname: Momčilović
authors.affiliation: Departments of Neurology, Human Genetics, and Pediatrics, School of Medicine, Emory University Atlanta, Georgia, 30322.
authors.forename: Hyder A
authors.initials: HA
authors.lastname: Jinnah
authors.affiliation: Department of Neurology, Loma Linda University Health System Loma Linda, California, 92354.
authors.forename: Karen
authors.initials: K
authors.lastname: Frei
authors.affiliation: Departments of Neurology and Anatomy & Neurobiology, University of Tennessee Health Science Center Memphis, Tennessee, 38163.
authors.forename: Ronald F
authors.initials: RF
authors.lastname: Pfeiffer
authors.affiliation: Departments of Neurology and Anatomy & Neurobiology, University of Tennessee Health Science Center Memphis, Tennessee, 38163.
authors.forename: Mark S
authors.initials: MS
authors.lastname: LeDoux
keywords: DYT6; Dystonia; THAP1; intronic variant; minigene assay