Unraveling Molecular Mechanisms of THAP1 Missense Mutations in DYT6 Dystonia

摘要: Mutations in THAP1 (THAP domain-containing apoptosis-associated protein 1) are responsible for DYT6 dystonia. Until now, more than eighty different mutations gene have been found patients with primary dystonia, and two third of them missense mutations. The potential pathogeneses these human largely elusive. In the present study, we generated stable transfected neuronal cell lines expressing wild-type or mutated proteins patients. Transcriptional profiling using microarrays revealed a set 28 common genes dysregulated (S21T F81L) overexpression suggesting mechanism ChIP-seq showed that can bind to promoter one genes, superoxide dismutase 2 (SOD2). Overexpression SK-N-AS cells resulted increased SOD2 expression, whereas fibroblasts from less which indicates is direct target THAP1. addition, show some (C54Y decrease stability might also be altered transcription regulation due dosage insufficiency. Taking together, current study pathogenic mechanisms lead same consequence