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ABSTRACT

Mutations in THAP1 have been associated with dystonia 6. THAP1 encodes a transcription factor with mostly unknown targets. We tested the hypothesis that THAP1 regulates the expression of DYT1 (TOR1A), another dystonia-causing gene. After characterization of the TOR1A promoter, we demonstrate that THAP1 binds to the core promoter of TOR1A. Further, we report that wild type THAP1 represses the expression of TOR1A, whereas dystonia 6-associated mutant THAP1 results in decreased repression of TOR1A. Our data demonstrate that THAP1 regulates the transcription of TOR1A, suggesting transcriptional dysregulation as a cause of dystonia.

Subject(s)

Apoptosis Regulatory Proteins/metabolism , DNA-Binding Proteins/metabolism , Dystonic Disorders/genetics , Gene Expression Regulation/genetics , Molecular Chaperones/genetics , Nuclear Proteins/metabolism , Adult , Aged , Apoptosis Regulatory Proteins/genetics , Cells, Cultured , Chromatin Immunoprecipitation/methods , DNA-Binding Proteins/genetics , Dystonic Disorders/pathology , Female , Fibroblasts/drug effects , Fibroblasts/metabolism , Gene Expression Regulation/drug effects , Humans , Male , Middle Aged , Molecular Chaperones/metabolism , Mutation, Missense/genetics , Neuroblastoma/pathology , Nuclear Proteins/genetics , RNA, Messenger/metabolism , RNA, Small Interfering/pharmacology , Transfection/methods

ABSTRACT

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