| Literature DB >> 29474918 |
Tatsiana Aneichyk1, William T Hendriks2, Rachita Yadav1, David Shin2, Dadi Gao1, Christine A Vaine2, Ryan L Collins3, Aloysius Domingo4, Benjamin Currall5, Alexei Stortchevoi5, Trisha Multhaupt-Buell2, Ellen B Penney2, Lilian Cruz2, Jyotsna Dhakal2, Harrison Brand5, Carrie Hanscom5, Caroline Antolik5, Marisela Dy2, Ashok Ragavendran5, Jason Underwood6, Stuart Cantsilieris7, Katherine M Munson7, Evan E Eichler8, Patrick Acuña2, Criscely Go9, R Dominic G Jamora10, Raymond L Rosales11, Deanna M Church12, Stephen R Williams12, Sarah Garcia12, Christine Klein13, Ulrich Müller14, Kirk C Wilhelmsen15, H T Marc Timmers16, Yechiam Sapir17, Brian J Wainger17, Daniel Henderson2, Naoto Ito2, Neil Weisenfeld18, David Jaffe18, Nutan Sharma2, Xandra O Breakefield2, Laurie J Ozelius2, D Cristopher Bragg19, Michael E Talkowski20.
Abstract
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.Entities:
Keywords: DYT3; Parkinson’s disease; SVA; TAF1; XDP; dystonia; genome assembly; intron retention; retrotransposon; transcriptome assembly
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Year: 2018 PMID： 29474918 PMCID： PMC5831509 DOI： 10.1016/j.cell.2018.02.011
Source DB: PubMed Journal: Cell ISSN： 0092-8674 Impact factor: 66.850