Journal
CELL
Volume 172, Issue 5, Pages 897-+Publisher
CELL PRESS
DOI: 10.1016/j.cell.2018.02.011
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Funding
- MGH Department of Pathology Flow and Image Cytometry Research Core [1S10OD012027-01A1, 1S10OD016372-01, 1S10RR020936-01, 1S10RR023440-01A1]
- MGH Collaborative Center for X-Linked Dystonia-Parkinsonism
- National Institutes of Health [R01NS102423, 5P01NS087997, UM1HG008900]
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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.
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