A rare sequence variant in intron 1 of THAP1 is associated with primary dystonia.

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

doi:10.1002/mgg3.67

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.

Highlights

Dystonia is a neurological disorder characterized by sustained or intermittent involuntary muscle contractions leading to abnormal postures and movements that may be tremulous (Fahn et al 1998; Albanese et al 2013)
Our study investigated the effects of a sequence variant (c.71+9C>A, rs200209986) located within Intron 1 of THAP1 on gene splicing and gene expression in subjects with primary dystonia
This Minor allele frequencies (MAFs) is similar to data from the 1000 Genomes but lower than the MAF reported by the Exome Variant Server (EVS) database

Summary

Introduction

Dystonia is a neurological disorder characterized by sustained or intermittent involuntary muscle contractions leading to abnormal postures and movements that may be tremulous (Fahn et al 1998; Albanese et al 2013). Dystonia is classified along two axes: clinical characteristics and etiological categories. Clinical characteristics include age of onset, body distribution, temporal pattern, coexistence of other movement disorders, and other neurological manifestations (Fahn et al 1998; LeDoux 2012b; Albanese et al 2013). Etiological categories include nervous system pathology and inherited. Adult-onset dystonia without evidence of overt degeneration or structural lesions of the nervous system is referred to as primary or isolated dystonia and inherited in autosomal-dominant fashion with reduced penetrance (Fahn et al 1998; LeDoux 2012b). The role of large structural and noncoding variants in the etiopathogenesis of primary dystonia remains largely unexplored (Moscovich et al 2013)

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