Details

Autor(en) / Beteiligte

• Aneichyk, Tatsiana
• Hendriks, William T.
• Yadav, Rachita
• Shin, David
• Gao, Dadi
• Vaine, Christine A.
• Collins, Ryan L.
• Domingo, Aloysius
• Currall, Benjamin
• Stortchevoi, Alexei
• Multhaupt-Buell, Trisha
• Penney, Ellen B.
• Cruz, Lilian
• Dhakal, Jyotsna
• Brand, Harrison
• Hanscom, Carrie
• Antolik, Caroline
• Dy, Marisela
• Ragavendran, Ashok
• Underwood, Jason
• Cantsilieris, Stuart
• Munson, Katherine M.
• Eichler, Evan E.
• Acuña, Patrick
• Go, Criscely
• Jamora, R. Dominic G.
• Rosales, Raymond L.
• Church, Deanna M.
• Williams, Stephen R.
• Garcia, Sarah
• Klein, Christine
• Müller, Ulrich
• Wilhelmsen, Kirk C.
• Timmers, H. T. Marc
• Sapir, Yechiam
• Wainger, Brian J.
• Henderson, Daniel
• Ito, Naoto
• Weisenfeld, Neil
• Jaffe, David
• Sharma, Nutan
• Breakefield, Xandra O.
• Ozelius, Laurie J.
• Bragg, D. Cristopher
• Talkowski, Michael E.

Titel

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

Ist Teil von

• Cell, 2018-02, Vol.172 (5), p.897-909.e21

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2018

Link zum Volltext

Quelle

Free E-Journal (出版社公開部分のみ）

Beschreibungen/Notizen

• 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. [Display omitted] •Genome assembly narrows the causal XDP locus to TAF1•An XDP-specific SVA insertion causes intron retention and reduced expression of TAF1•CRISPR/Cas9 excision of SVA rescues aberrant splicing and TAF1 expression in XDP•Expression profiling implicates neurodevelopment and dystonia pathways in XDP A Mendelian form of dystonia arises from altered splicing and intron retention within a general transcription factor.