Specific sequence changes in multiple transcript system DYT3 are associated with X-linked dystonia parkinsonism

Abstract

X-linked dystonia parkinsonism (XDP) is an X-linked recessive adult onset movement disorder characterized by both dystonia and parkinsonism. We report delineation of the disease gene within a 300-kb interval of Xq13.1 by allelic association. Sequencing of this region in a patient revealed five disease-specific single-nucleotide changes (here referred to as DSC) and a 48-bp deletion unique to XDP. One of the DSCs is located within an exon of a not previously described multiple transcript system that is composed of at least 16 exons. There is a minimum of three different transcription start sites that encode four different transcripts. Two of these transcripts include distal portions of the TAF1 gene (TATA-box binding protein-associated factor 1) and are alternatively spliced. Three exons overlap with ING2 (a putative tumor suppressor) and with a homologue of CIS4 (cytokine-inducible SH2 protein 4), both of which are encoded by the opposite strand. Although all DSCs are located within this multiple transcript system, only DSC3 lies within an exon. This exon is used by all alternative transcripts making a pathogenic role of DSC3 in XDP likely. The multiple transcript system is therefore referred to as DYT3 (disease locus in XDP).X chromosome ͉ positional cloning ͉ single-nucleotide polymorphism ͉ alternative splicing ͉ transcription factor

New insights into the genetics of X-linked dystonia-parkinsonism (XDP, DYT3)

“…Later validation by Sanger sequencing confirmed that this allele was also present in controls (5/43 X-chromosomes). Notably, the paucity of variants found within the linked region is similar to previous sequencing studies 7,8 which used traditional methods (ie, not NGS) to sequence this locus. Outside of the linked region, we found no exonic SNV located on the X chromosome that is shared between G01-G04 and either G05 or G06.…”

“…15 Haplotype analysis using STR markers within or surrounding the disease locus (DXS10015, DXS10016, DXS10017, DXS10018, and DXS559) 7 were analyzed on polyacrylamide gels or on an ABI3130XL Genetic Analyzer running GeneMapper 4.0 software (Applied Biosystems). Primer sequences and conditions are available upon request.…”

“…[3][4][5][6] Instead, five disease-specific single-nucleotide changes (DSC1, DSC2, DSC3, DSC10, DSC12), one 48-bp deletion, and one 2627-bp SVA (SINE-VNTR-Alu element) retrotransposon insertion, all found either within 'deep intronic' or intergenic DNA segments, or in a nonconventional exon of the nearby TAF1 gene, have been identified only in affected individuals. 7,8 None of these diseaseassociated genetic variants are located in protein-coding segments based on current annotations of the human genome, although the regulation of neuron-specific TAF1 isoforms or of other genes in the region has been postulated as disease mechanisms. [7][8][9] Nevertheless, the exact disease-causing variant has been a matter of debate, [9][10][11][12] and theoretically, only one-if any-is functionally related to disease causation, whereas the remaining are merely benign variants.…”

“…7,8 None of these diseaseassociated genetic variants are located in protein-coding segments based on current annotations of the human genome, although the regulation of neuron-specific TAF1 isoforms or of other genes in the region has been postulated as disease mechanisms. [7][8][9] Nevertheless, the exact disease-causing variant has been a matter of debate, [9][10][11][12] and theoretically, only one-if any-is functionally related to disease causation, whereas the remaining are merely benign variants.…”

The genetics of the dystonias – a review based on the new classification of the dystonias

“…The DYT3 gene consists of at least 43 exons that are alternatively spliced. There are alternative transcripts of exons 1-38 that encode isoforms of the TATA-box binding protein-associated factor I (TAF-1) and five exons (d1-d5) downstream to exon 38 (multiple transcript system) 39 .…”