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 Ledoux

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)261-272
Number of pages12
JournalMolecular Genetics and Genomic Medicine
Volume2
Issue number3
DOIs
StatePublished - Jan 1 2014

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Dystonic Disorders
Introns
Protein Isoforms
G2 Phase
Computer Simulation
Cell Survival
Cell Cycle
Leukocytes
Cell Proliferation
Apoptosis
DNA
Growth
Genes

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

Cite this

A rare sequence variant in intron 1 of thap1 is associated with primary dystonia. / 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; Rudzinska, Monika; Momcilovic, Dragana; Jinnah, Hyder A.; Frei, Karen; Pfeiffer, Ronald F.; Ledoux, Mark.

In: Molecular Genetics and Genomic Medicine, Vol. 2, No. 3, 01.01.2014, p. 261-272.

Research output: Contribution to journalArticle

Vemula, SR, Xiao, J, Zhao, Y, Bastian, RW, Perlmutter, JS, Racette, BA, Paniello, RC, Wszolek, ZK, Uitti, RJ, Van Gerpen, JA, Hedera, P, Truong, DD, Blitzer, A, Rudzinska, M, Momcilovic, D, Jinnah, HA, Frei, K, Pfeiffer, RF & Ledoux, M 2014, 'A rare sequence variant in intron 1 of thap1 is associated with primary dystonia', Molecular Genetics and Genomic Medicine, vol. 2, no. 3, pp. 261-272. https://doi.org/10.1002/mgg3.67
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 ; Rudzinska, Monika ; Momcilovic, Dragana ; Jinnah, Hyder A. ; Frei, Karen ; Pfeiffer, Ronald F. ; Ledoux, Mark. / A rare sequence variant in intron 1 of thap1 is associated with primary dystonia. In: Molecular Genetics and Genomic Medicine. 2014 ; Vol. 2, No. 3. pp. 261-272.
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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.",
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AU - Uitti, Ryan J.

AU - Van Gerpen, Jay A.

AU - Hedera, Peter

AU - Truong, Daniel D.

AU - Blitzer, Andrew

AU - Rudzinska, Monika

AU - Momcilovic, Dragana

AU - Jinnah, Hyder A.

AU - Frei, Karen

AU - Pfeiffer, Ronald F.

AU - Ledoux, Mark

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