RT Journal Article
SR Electronic
T1 Dissecting the Causal Mechanism of X-Linked Dystonia-Parkinsonism by Integrating Genome and Transcriptome Assembly
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 149872
DO 10.1101/149872
A1 Tatsiana Aneichyk
A1 William.T. Hendriks
A1 Rachita Yadav
A1 David Shin
A1 Dadi Gao
A1 Christine A. Vaine
A1 Ryan L. Collins
A1 Alexei Stortchevoi
A1 Benjamin Currall
A1 Harrison Brand
A1 Carrie Hanscom
A1 Caroline Antolik
A1 Marisela Dy
A1 Ashok Ragavendran
A1 Patrick Acuña
A1 Criscely Go
A1 Yechiam Sapir
A1 Brian J. Wainger
A1 Daniel Henderson
A1 Jyotsna Dhakal
A1 Naoto Ito
A1 Neil Weisenfeld
A1 David Jaffe
A1 Nutan Sharma
A1 Xandra O. Breakefield
A1 Laurie J. Ozelius
A1 D. Cristopher Bragg
A1 Michael E. Talkowski
YR 2017
UL http://biorxiv.org/content/early/2017/06/14/149872.abstract
AB X-linked Dystonia-Parkinsonism (XDP) is a Mendelian neurodegenerative disease endemic to the Philippines. We integrated genome and transcriptome assembly with induced pluripotent stem cell-based modeling to identify the XDP causal locus and potential pathogenic mechanism. Genome sequencing identified novel variation that was shared by all probands and three recombination events that narrowed the causal locus to a genomic segment including TAF1. Transcriptome assembly in neural derivative cells discovered novel TAF1 transcripts, including a truncated transcript exclusively observed in probands that involved aberrant splicing and intron retention (IR) associated with a SINE-VNTR-Alu (SVA)-type retrotransposon insertion. This IR correlated with decreased expression of the predominant TAF1 transcript and altered expression of neurodevelopmental genes; both the IR and aberrant TAF1 expression patterns were rescued by CRISPR/Cas9 excision of the SVA. These data suggest a unique genomic cause of XDP and may provide a roadmap for integrative genomic studies in other unsolved Mendelian disorders.Highlights Genome assembly narrows the XDP causal locus to a segment including TAF1XDP-specific SVA insertion induces intron retention and down-regulation of TAF1CRISPR/Cas9 excision of SVA rescues aberrant splicing and cTAF1 expression in XDPGene networks perturbed in proband cells associate to synapse and neurodevelopment