A rare sequence variant in intron 1 of THAP1 is associated with primary dystonia. Issue 3 (11th February 2014)

• Record Type: Journal Article
• Authors: Vemula, Satya R.; Xiao, Jianfeng; Zhao, Yu; Bastian, Robert W.; Perlmutter, Joel S.; Racette, Brad A.; Paniello, Randal C.; Wszolek, Zbigniew K.; Uitti, Ryan J.; Van Gerpen, Jay A.; Hedera, Peter; Truong, Daniel D.; Blitzer, Andrew; Rudzińska, Monika; Momčilović, Dragana; Jinnah, Hyder A.; Frei, Karen; Pfeiffer, Ronald F.; LeDoux, Mark S.
• Is Part Of: Molecular genetics & genomic medicine. Volume 2:Issue 3(2014:May)
• Page Start: 261
• Page End: 272
• Publication Date: 2014-02-11
• Subjects: Medical genetics -- Periodicals; Genomics -- Periodicals; 616.042
• DOI: 10.1002/mgg3.67
• Languages: English
• ISSNs: 2324-9269

Abstract

<abstract abstract-type="main" id="mgg367-abs-0001"> <title>Abstract</title> <p>Although coding variants in <italic>THAP1</italic> 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 (<italic>P </italic><<italic> </italic>0.01). Dystonia classification included cervical dystonia (<italic>N</italic> = 3), laryngeal dystonia (adductor subtype, <italic>N</italic> = 3), jaw‐opening oromandibular dystonia (<italic>N</italic> = 1), blepharospasm (<italic>N</italic> = 2), and unclassified (<italic>N</italic> = 3). Age of dystonia onset ranged from 25 to 69 years (mean = 54 years). In comparison to controls with no identified <italic>THAP1</italic> 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 <italic>THAP1</italic> 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 <italic>THAP1</italic> c.71+9C>A is a risk factor for adult‐onset primary dystonia.</p> </abstract>