Analysis of the physiological and pathological function of DYT3, a multiple transcript system mutated in the X-linked dystonia parkinsonism syndrome (XDP)

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The X-linked dystonia-parkinsonism syndrome (XDP) is a severe movement disorder characterized by distonia and parkinsonism. The disorder is genetically homogeneous and has been exclusively diagnosed in patients in Filipino descent. XDP is caused by one or more disease-specific single-nucleotide changes (DSCs) in a novel mulitple transcript system, DYT3, located in Xq13.1 DYT3 is composed of at least 16 exons and there is a minimum of three transcription start sites that encode four different transcripts. Two of these transcripts include distal portions of TAF1 (TATA-box binding protein - associated factor 1) and are alternatively spliced. There are 5 DSCs within DYT3 one of which lies within an exon utilized by all alternative transcripts. We will study both physiological and pathological function of DYT3 by 1) Complete analysis of all alternative transcripts of DYT3 and of their transcription start sites; 2) Quantification of alternative transcripts; 3) Investigation of possible translation of parts of DYT3; 4) Elucidation of the effects of DSCs on expression of other genes using Affymetrix expression arrays.