A rare sequence variant in intron 1 of thap1 is associated with primary dystonia

Satya R. Vemula, Jianfeng Xiao, Yu Zhao, Robert W. Bastian, Joel S. Perlmutter, Brad A. Racette, Randal C. Paniello, Zbigniew K. Wszolek, Ryan J. Uitti, Jay A. Van Gerpen, Peter Hedera, Daniel D. Truong, Andrew Blitzer, Monika Rudzinska, Dragana Momcilovic, Hyder A. Jinnah, Karen Frei, Ronald F. Pfeiffer, Mark S. Ledoux

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18 Scopus citations


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.

Original languageEnglish
Pages (from-to)261-272
Number of pages12
JournalMolecular Genetics and Genomic Medicine
Issue number3
StatePublished - May 2014


  • DYT6
  • Dystonia
  • Intronic variant
  • Minigene assay
  • THAP1


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