Open AccessA rare sequence variant in intron 1 of THAP 1 is associated with primary dystonia
Author(s) -
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.,
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.
Publication year - 2014
Publication title -
molecular genetics and genomic medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.765
H-Index - 29
ISSN - 2324-9269
DOI - 10.1002/mgg3.67
Subject(s) - dystonia , minigene , blepharospasm , cervical dystonia , intron , biology , mutation , rna splicing , exon , genetics , medicine , gene , alternative splicing , microbiology and biotechnology , neuroscience , rna
Although coding variants in THAP 1 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 THAP 1 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 THAP 1 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 THAP 1 c.71+9C>A is a risk factor for adult‐onset primary dystonia.