Dissecting the Causal Mechanism of X-Linked Dystonia-Parkinsonism by Integrating Genome and Transcriptome Assembly

Tatsiana Aneichyk, William T. Hendriks, Rachita Yadav, David Shin, Dadi Gao, Christine A. Vaine, Ryan L. Collins, Aloysius Domingo, Benjamin Currall, Alexei Stortchevoi, Trisha Multhaupt-Buell, Ellen B. Penney, Lilian Cruz, Jyotsna Dhakal, Harrison Brand, Carrie Hanscom, Caroline Antolik, Marisela Dy, Ashok Ragavendran, Jason UnderwoodStuart Cantsilieris, Katherine M. Munson, Evan E. Eichler, Patrick Acuña, Criscely Go, R. Dominic G. Jamora, Raymond L. Rosales, Deanna M. Church, Stephen R. Williams, Sarah Garcia, Christine Klein, Ulrich Müller, Kirk C. Wilhelmsen, H. T.Marc Timmers, Yechiam Sapir, Brian J. Wainger, Daniel Henderson, Naoto Ito, Neil Weisenfeld, David Jaffe, Nutan Sharma, Xandra O. Breakefield, Laurie J. Ozelius, D. Cristopher Bragg*, Michael E. Talkowski

*Corresponding author for this work
25 Citations (Scopus)


X-linked Dystonia-Parkinsonism (XDP) is a Mendelian neurodegenerative disease that is endemic to the Philippines and is associated with a founder haplotype. We integrated multiple genome and transcriptome assembly technologies to narrow the causal mutation to the TAF1 locus, which included a SINE-VNTR-Alu (SVA) retrotransposition into intron 32 of the gene. Transcriptome analyses identified decreased expression of the canonical cTAF1 transcript among XDP probands, and de novo assembly across multiple pluripotent stem-cell-derived neuronal lineages discovered aberrant TAF1 transcription that involved alternative splicing and intron retention (IR) in proximity to the SVA that was anti-correlated with overall TAF1 expression. CRISPR/Cas9 excision of the SVA rescued this XDP-specific transcriptional signature and normalized TAF1 expression in probands. These data suggest an SVA-mediated aberrant transcriptional mechanism associated with XDP and may provide a roadmap for layered technologies and integrated assembly-based analyses for other unsolved Mendelian disorders. A Mendelian form of dystonia arises from altered splicing and intron retention within a general transcription factor.

Original languageEnglish
Issue number5
Pages (from-to)897-909
Number of pages13
Publication statusPublished - 22.02.2018

Research Areas and Centers

  • Research Area: Medical Genetics


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