Dissecting the Causal Mechanism of X-Linked Dystonia-Parkinsonism by Integrating Genome and Transcriptome Assembly.
Dissecting the Causal Mechanism of X-Linked Dystonia-Parkinsonism by Integrating Genome and Transcriptome Assembly.
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DOI：
10.1016/j.cell.2018.02.011
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发表时间：
2018-02-22
期刊：
影响因子：
64.5
通讯作者：
Talkowski ME
中科院分区：
文献类型：
--
作者：
Aneichyk 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;Jamora RDG;Rosales RL;Church DM;Williams SR;Garcia S;Klein C;Müller U;Wilhelmsen KC;Timmers HTM;Sapir Y;Wainger BJ;Henderson D;Ito N;Weisenfeld N;Jaffe D;Sharma N;Breakefield XO;Ozelius LJ;Bragg DC;Talkowski ME
X连锁肌张力障碍-帕金森综合征（XDP）是菲律宾特有的孟德尔神经退行性疾病，与创始人单倍型相关。我们整合了多基因组和转录组组装技术，以缩小TAF 1基因座的因果突变，其中包括SINE-VNTR-Alu（SVA）反转录转座到基因的内含子32。转录组分析确定了XDP先证者中典型cTAF 1转录物的表达降低，并且多个多能干细胞衍生的神经元谱系的从头组装发现了异常TAF 1转录，其涉及与总体TAF 1表达反相关的SVA附近的选择性剪接和内含子保留（IR）。CRISPR/Cas9切除SVA挽救了这种XDP特异性转录特征，并使先证者的TAF 1表达正常化。这些数据表明SVA介导的异常转录机制与XDP相关，并可能为分层技术和其他未解决的孟德尔疾病的集成组装分析提供路线图。一种孟德尔形式的帕金森病是由一个普通转录因子内剪接和内含子保留的改变引起的。
X-linked Dystonia-Parkinsonism (XDP) is a Mendelian neurodegenerative disease that is endemic to the Philippines and 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. A Mendelian form of parkinsonism arises from altered splicing and intron retention within a general transcription factor.
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影响因子：
5.8
作者：
Barnett, Derek W.;Garrison, Erik K.;Marth, Gabor T.
通讯作者：
Marth, Gabor T.
DOI：
10.1093/bioinformatics/btu638
发表时间：
2015-01-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
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作者：
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通讯作者：
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作者：
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通讯作者：
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通讯作者：
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