February 25, 2021  |  

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

Authors: Aneichyk, and T., and Hendriks, and W. T., and Yadav, and R., and Shin, and D., and Gao, and D., and Vaine, and C. A., and Collins, and R. L., and Domingo, and A., and Currall, and B., and Stortchevoi, and A., and Multhaupt-Buell, and T., and Penney, and E. B., and Cruz, and L., and Dhakal, and J., and Brand, and H., and Hanscom, and C., and Antolik, and C., and Dy, and M., and Ragavendran, and A., and Underwood, and J., and … Talkowski, and M. E. 

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.

Journal: Cell
DOI: 10.1016/j.cell.2018.02.011
Year: 2018

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