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

被引：173

作者：

Aneichyk, Tatsiana ^{[1
,2
,3
,4
,5
]}

Hendriks, William T. ^{[2
,3
,6
]}

Yadav, Rachita ^{[1
,2
,3
,4
,5
]}

Shin, David ^{[2
,3
,6
]}

Gao, Dadi ^{[1
,2
,3
,4
,5
]}

Vaine, Christine A. ^{[2
,3
,6
]}

Collins, Ryan L. ^{[1
,4
,5
]}

Domingo, Aloysius ^{[1
,2
,3
,4
,5
,6
]}

Currall, Benjamin ^{[1
,2
,3
]}

Stortchevoi, Alexei ^{[1
,2
,3
]}

Multhaupt-Buell, Trisha ^{[2
,3
,6
]}

Penney, Ellen B. ^{[2
,3
,6
]}

Cruz, Lilian ^{[2
,3
,6
]}

Dhakal, Jyotsna ^{[2
,3
,6
]}

Brand, Harrison ^{[1
,2
,3
]}

Hanscom, Carrie ^{[1
,2
,3
]}

Antolik, Caroline ^{[1
,2
,3
]}

Dy, Marisela ^{[2
,3
,6
]}

Ragavendran, Ashok ^{[1
,2
,3
]}

Underwood, Jason ^{[7
,8
]}

Cantsilieris, Stuart ^{[8
]}

Munson, Katherine M. ^{[8
]}

Eichler, Evan E. ^{[8
,9
]}

Acuna, Patrick ^{[2
,3
,6
]}

Go, Criscely ^{[10
]}

Jamora, R. Dominic G. ^{[11
]}

Rosales, Raymond L. ^{[12
]}

Church, Deanna M. ^{[13
]}

Williams, Stephen R. ^{[13
]}

Garcia, Sarah ^{[13
]}

Klein, Christine ^{[14
]}

Mueller, Ulrich ^{[15
]}

Wilhelmsen, Kirk C. ^{[16
]}

Timmers, H. T. Marc ^{[17
,18
]}

Sapir, Yechiam ^{[2
,3
]}

Wainger, Brian J. ^{[2
,3
]}

Henderson, Daniel ^{[2
,3
,6
]}

Ito, Naoto ^{[2
,3
,6
]}

Weisenfeld, Neil ^{[13
,19
]}

Jaffe, David ^{[13
,19
]}

Sharma, Nutan ^{[2
,3
,6
]}

Breakefield, Xandra O. ^{[2
,3
,6
]}

Ozelius, Laurie J. ^{[2
,3
,6
]}

Bragg, D. Cristopher ^{[2
,3
,6
]}

Talkowski, Michael E. ^{[1
,2
,3
,4
,5
,6
,20
,21
]}

机构：

[1] Massachusetts Gen Hosp, Ctr Genom Med, Boston, MA 02114 USA

[2] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA

[3] Harvard Med Sch, Boston, MA 02114 USA

[4] Broad Inst, Program Med & Populat Genet, Cambridge, MA 02142 USA

[5] Broad Inst, Stanley Ctr Psychiat Res, Cambridge, MA 02142 USA

[6] Massachusetts Gen Hosp, Collaborat Ctr X Linked Dystonia Parkinsonism, Charlestown, MA 02129 USA

[7] Pacific Biosci, Menlo Pk, CA 94025 USA

[8] Univ Washington, Sch Med, Dept Genome Sci, Seattle, WA 98195 USA

[9] Howard Hughes Med Inst, Seattle, WA 98195 USA

[10] Jose Reyes Mem Med Ctr, Manila, Philippines

[11] Philippine Gen Hosp, Manila, Philippines

[12] Univ Santo Tomas Hosp, Manila, Philippines

[13] 10X Genomics, Pleasanton, CA 94566 USA

[14] Univ Lubeck, Inst Neurogenet, Lubeck, Germany

[15] Justus Liebig Univ, Inst Humangenet, Giessen, Germany

[16] Univ North Carolina Chapel Hill, Chapel Hill, NC 27599 USA

[17] Univ Med Ctr, German Canc Consortium DKTK Partner Site Freiburg, Freiburg, Germany

[18] Univ Med Ctr, Dept Urol, Freiburg, Germany

[19] Broad Inst, Genome Sequencing & Anal Program, Cambridge, MA 02142 USA

[20] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA

[21] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA

来源：

CELL | 2018年 / 172卷 / 05期

基金：

美国国家卫生研究院;

关键词：

INTRON RETENTION; VARIATION DISCOVERY; GENE; RNA; EXPRESSION; TAF1; FRAMEWORK; ALIGNMENT;

D O I：

10.1016/j.cell.2018.02.011

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：897 / +

页数：34

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