Disease onset in X-linked dystonia-parkinsonism correlates with expansion of a hexameric repeat within an SVA retrotransposon in TAF1

D. Cristopher Bragg, Kotchaphorn Mangkalaphiban, Christine A. Vaine, Nichita J. Kulkarni, David Shin, Rachita Yadav, Jyotsna Dhakal, Mai Linh Ton, Anne Cheng, Christopher T. Russo, Mark Ang, Patrick Acuña, Criscely Go, Taylor N. Franceour, Trisha Multhaupt-Buell, Naoto Ito, Ulrich Müller, William T. Hendriks, Xandra O. Breakefield, Nutan SharmaLaurie J. Ozelius, Solomon H. Snyder

Research output: Contribution to journalArticlepeer-review

54 Scopus citations


X-linked dystonia-parkinsonism (XDP) is a neurodegenerative disease associated with an antisense insertion of a SINE-VNTR-Alu (SVA)-type retrotransposon within an intron of TAF1. This unique insertion coincides with six additional noncoding sequence changes in TAF1, the gene that encodes TATA-binding protein-associated factor-1, which appear to be inherited together as an identical haplotype in all reported cases. Here we examined the sequence of this SVA in XDP patients (n = 140) and detected polymorphic variation in the length of a hexanucleotide repeat domain, (CCCTCT)n. The number of repeats in these cases ranged from 35 to 52 and showed a highly significant inverse correlation with age at disease onset. Because other SVAs exhibit intrinsic promoter activity that depends in part on the hexameric domain, we assayed the transcriptional regulatory effects of varying hexameric lengths found in the unique XDP SVA retrotransposon using luciferase reporter constructs. When inserted sense or antisense to the luciferase reading frame, the XDP variants repressed or enhanced transcription, respectively, to an extent that appeared to vary with length of the hexamer. Further in silico analysis of this SVA sequence revealed multiple motifs predicted to form G-quadruplexes, with the greatest potential detected for the hexameric repeat domain. These data directly link sequence variation within the XDP-specific SVA sequence to phenotypic variability in clinical disease manifestation and provide insight into potential mechanisms by which this intronic retroelement may induce transcriptional interference in TAF1 expression.

Original languageEnglish (US)
Pages (from-to)E11020-E11028
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number51
StatePublished - Dec 19 2017


  • DYT3
  • Dystonia
  • Parkinson's disease
  • TAF1
  • XDP

ASJC Scopus subject areas

  • General


Dive into the research topics of 'Disease onset in X-linked dystonia-parkinsonism correlates with expansion of a hexameric repeat within an SVA retrotransposon in TAF1'. Together they form a unique fingerprint.

Cite this