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

TitleDissecting the Causal Mechanism of X-Linked Dystonia-Parkinsonism by Integrating Genome and Transcriptome Assembly.
Publication TypeJournal Article
Year of Publication2018
AuthorsAneichyk, T, Hendriks, WT, Yadav, R, Shin, D, Gao, D, Vaine, CA, Collins, RL, Domingo, A, Currall, B, Stortchevoi, A, Multhaupt-Buell, T, Penney, EB, Cruz, L, Dhakal, J, Brand, H, Hanscom, C, Antolik, C, Dy, M, Ragavendran, A, Underwood, J, Cantsilieris, S, Munson, KM, Eichler, EE, Acuña, P, Go, C, R Jamora, DG, Rosales, RL, Church, DM, Williams, SR, Garcia, S, Klein, C, Müller, U, Wilhelmsen, KC, Timmers, HTMarc, Sapir, Y, Wainger, BJ, Henderson, D, Ito, N, Weisenfeld, N, Jaffe, D, Sharma, N, Breakefield, XO, Ozelius, LJ, D Bragg, C, Talkowski, ME
Date Published2018 02 22
KeywordsAlternative Splicing, Alu Elements, Base Sequence, Cohort Studies, CRISPR-Cas Systems, Dystonic Disorders, Family, Female, Genetic Diseases, X-Linked, Genetic Loci, Genome, Human, Haplotypes, High-Throughput Nucleotide Sequencing, Histone Acetyltransferases, Humans, Induced Pluripotent Stem Cells, Introns, Male, Minisatellite Repeats, Models, Genetic, Nerve Degeneration, Neural Stem Cells, Neurons, RNA, Messenger, Short Interspersed Nucleotide Elements, TATA-Binding Protein Associated Factors, Transcription Factor TFIID, Transcriptome

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.

Alternate JournalCell
PubMed ID29474918
PubMed Central IDPMC5831509
Grant ListP01 NS087997 / NS / NINDS NIH HHS / United States
UM1 HG008900 / HG / NHGRI NIH HHS / United States
/ HH / Howard Hughes Medical Institute / United States
R01 NS102423 / NS / NINDS NIH HHS / United States
S10 RR023440 / RR / NCRR NIH HHS / United States
S10 RR020936 / RR / NCRR NIH HHS / United States
S10 OD016372 / OD / NIH HHS / United States
S10 OD012027 / OD / NIH HHS / United States