Germline gain-of-function mutations in AFF4 cause a developmental syndrome functionally linking the super elongation complex and cohesin.
Germline gain-of-function mutations in AFF4 cause a developmental syndrome functionally linking the super elongation complex and cohesin.
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DOI：
10.1038/ng.3229
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发表时间：
2015-04
期刊：
影响因子：
30.8
通讯作者：
Krantz, Ian D.
中科院分区：
文献类型：
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作者：
Izumi, Kosuke;Nakato, Ryuichiro;Zhang, Zhe;Edmondson, Andrew C.;Noon, Sarah;Dulik, Matthew C.;Rajagopalan, Ramakrishnan;Venditti, Charles P.;Gripp, Karen;Samanich, Joy;Zackai, Elaine H.;Deardorff, Matthew A.;Clark, Dinah;Allen, Julian L.;Dorsett, Dale;Misulovin, Ziva;Komata, Makiko;Bando, Masashige;Kaur, Maninder;Katou, Yuki;Shirahige, Katsuhiko;Krantz, Ian D.
转录延伸是胚胎发育过程中基因表达调控的关键。超延长复合体(SEC)通过动员暂停的RNA聚合酶II(RNAP2)来控制这一过程。利用外显子测序技术，我们在三个无关的先证者中发现了AFF4的错义突变，这些先证者患有一种新的综合征，表型与Cornelia de Lange综合征(CDLS)重叠，我们将其命名为CHOPS综合征(C代表认知障碍和粗略相，H代表心脏缺陷，O代表肥胖，P代表肺损害，S代表矮小和骨骼发育不良)。转录组和染色质免疫沉淀测序(ChIP-seq)分析显示CDLS和CHOPS综合征之间AFF4、粘附素和RNAP2的全基因组结合改变相似。SEC、粘附素和RNAP2之间存在直接的分子相互作用。这一数据支持CHOPS综合征和CDLS的共同分子发病机制，该疾病是由于AFF4和粘附素全基因组结合的改变而导致转录延长障碍引起的。
Transcriptional elongation is critical for gene expression regulation during embryogenesis. The super elongation complex (SEC) governs this process by mobilizing paused RNA polymerase II (RNAP2). Using exome sequencing, we discovered missense mutations in AFF4, a core component of the SEC in three unrelated probands with a novel syndrome that phenotypically overlaps Cornelia de Lange syndrome (CdLS), that we have named CHOPS syndrome (C for Cognitive impairment and Coarse facies, H for Heart defects, O for Obesity, P for Pulmonary involvement and S for Short stature and Skeletal dysplasia). Transcriptome and chromatin immunoprecipitation sequencing (ChIP-seq) analyses demonstrated similar alterations of genome-wide binding of AFF4, cohesin and RNAP2 between CdLS and CHOPS syndrome. Direct molecular interaction between SEC, cohesin and RNAP2 was demonstrated. This data supports a common molecular pathogenesis for CHOPS syndrome and CdLS caused by disturbance of transcriptional elongation due to alterations in genome-wide binding of AFF4 and cohesin.
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影响因子：
1.2
作者：
Cingolani, Pablo;Platts, Adrian;Ruden, Douglas M.
通讯作者：
Ruden, Douglas M.
影响因子：
64.8
作者：
Nguyen, VT;Kiss, TS;Bensaude, O
通讯作者：
Bensaude, O
影响因子：
16
作者：
Lin, Chengqi;Smith, Edwin R.;Takahashi, Hidehisa;Lai, Ka Chun;Martin-Brown, Skylar;Florens, Laurence;Washburn, Michael P.;Conaway, Joan W.;Conaway, Ronald C.;Shilatifard, Ali
通讯作者：
Shilatifard, Ali
影响因子：
9.8
作者：
Deardorff, Matthew A.;Kaur, Maninder;Krantz, Ian D.
通讯作者：
Krantz, Ian D.
使用下一代 DNA 测序数据进行变异发现和基因分型的框架。
影响因子：
30.8
作者：
通讯作者：
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