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DYT6 dystonia is an autosomal dominant primary dystonia causally-associated with sequence variants in THAP1 which encodes the DNA-binding transcription factor THAP1.1–3 DYT6 dystonia shows reduced penetrance and variable expressivity.2–8 In contrast to DYT1 dystonia, DYT6 more commonly remains focal in distribution and often affects the cervical and laryngeal musculature.1,4,5 Over 30 sequence variants have been localized to the coding regions of THAP1 and associated with focal, segmental, multi-focal or generalized dystonia with age of onset ranging from 2 to 62 years.1–8 In addition, several asymptomatic carriers have been identified in the relatives of probands. The genetic and phenotypic heterogeneity of DYT6 dystonia, and variable penetrance of known coding variants suggest that non-coding variants in THAP1 could contribute to the risk of developing adult-onset primary dystonia.4,5,7 Given that THAP1 is a transcriptional repressor, it is conceivable that non-coding variants which cause minor quantitative changes in the temporal or spatial patterns of THAP1 expression could have broad effects on the transcriptome. Djarmati and colleagues4 identified a non-coding sequence variant (c.-237_236GA>TT) near the transcriptional start site of THAP1 that might increase the risk of developing primary dystonia. The relative frequency of this polymorphism in their subjects with dystonia (20/320) relative to controls (7/355) was noteworthy (P = 0.0054). Extrapolation of their findings to a broad population of late-onset primary dystonia is problematic given that the subjects with dystonia were relatively young (mean age of onset = 38.5 years) and predominantly Northern German whereas the control group was composed of Caucasian individuals of more diverse European ancestry. Another, relatively small case-control study with heterogeneous control and dystonia populations did not find an association between the TT allele and risk for dystonia.7 Herein, we present the results of a large case-control study of c.-237_236GA>TT in primary, mainly adult-onset, dystonia. All subjects were Caucasians. Moreover, the effects of the TT variant on overall gene expression (transcript) were interrogated in leukocytes, and replicated in lymphoblastoid cell lines (transcript and protein) derived from distinct cohorts of cases and controls. Although RNA derived from peripheral blood has been used to study DYT1 dystonia9 and other movement disorders, analysis of gene expression in lymphoblastoid cell lines limits potential exogenous confounds including the effects of medications, nutrient intake, and concomitant infectious and inflammatory medical conditions. |
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