De novo mutations in MED13, a component of the Mediator complex, are associated with a novel neurodevelopmental disorder.
De novo mutations in MED13, a component of the Mediator complex, are associated with a novel neurodevelopmental disorder.
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DOI：
10.1007/s00439-018-1887-y
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发表时间：
2018-05
期刊：
影响因子：
5.3
通讯作者：
Cooper GM
中科院分区：
文献类型：
--
作者：
Snijders Blok L;Hiatt SM;Bowling KM;Prokop JW;Engel KL;Cochran JN;Bebin EM;Bijlsma EK;Ruivenkamp CAL;Terhal P;Simon MEH;Smith R;Hurst JA;DDD study;McLaughlin H;Person R;Crunk A;Wangler MF;Streff H;Symonds JD;Zuberi SM;Elliott KS;Sanders VR;Masunga A;Hopkin RJ;Dubbs HA;Ortiz-Gonzalez XR;Pfundt R;Brunner HG;Fisher SE;Kleefstra T;Cooper GM
许多导致发育迟缓和/或智力残疾(DD/ID)的遗传原因极其罕见，而对这些原因的有力发现需要大规模的DNA测序和数据共享。在这里，我们描述了GeneMatcher的合作，它导致了13个受影响的个体在MED13中携带蛋白质改变变异，其中11个是从头开始的；唯一的遗传变异是从受影响的母亲传染给受影响的孩子。所有患者都有智力残疾和/或发育迟缓，包括语言迟缓或障碍。在两名或两名以上患者中报告的其他特征包括自闭症谱系障碍、注意缺陷多动障碍、视神经异常、Duane异常、低眼压、轻度先天性心脏异常和畸形。6个受影响的个体具有预测截断MED13蛋白的突变，6个个体具有错义突变，1个个体具有一种氨基酸的框内缺失。在七个非截断突变中，有六个聚集在MED13蛋白的两个特定位置：N末端和C末端区域。这四个N-末端聚集突变影响两个相邻的氨基酸，已知参与MED13泛素化和降解，p.Thr326和p.Pro327。MED13是CDK8-激酶模块的一个组成部分，可以可逆地结合介体，介体是聚合酶II转录启动所需的多蛋白复合体。此前已经证明，编码Mediator亚单位的其他几个基因的突变与DD/ID有关，包括MED13L，MED13的一个平行对数。因此，我们的发现将MED13添加到CDK8-激酶模块相关的疾病基因组中。本文的在线版本(10.1007/s00439-0181887-y)包含向授权用户提供的补充材料。
Many genetic causes of developmental delay and/or intellectual disability (DD/ID) are extremely rare, and robust discovery of these requires both large-scale DNA sequencing and data sharing. Here we describe a GeneMatcher collaboration which led to a cohort of 13 affected individuals harboring protein-altering variants, 11 of which are de novo, in MED13; the only inherited variant was transmitted to an affected child from an affected mother. All patients had intellectual disability and/or developmental delays, including speech delays or disorders. Other features that were reported in two or more patients include autism spectrum disorder, attention deficit hyperactivity disorder, optic nerve abnormalities, Duane anomaly, hypotonia, mild congenital heart abnormalities, and dysmorphisms. Six affected individuals had mutations that are predicted to truncate the MED13 protein, six had missense mutations, and one had an in-frame-deletion of one amino acid. Out of the seven non-truncating mutations, six clustered in two specific locations of the MED13 protein: an N-terminal and C-terminal region. The four N-terminal clustering mutations affect two adjacent amino acids that are known to be involved in MED13 ubiquitination and degradation, p.Thr326 and p.Pro327. MED13 is a component of the CDK8-kinase module that can reversibly bind Mediator, a multi-protein complex that is required for Polymerase II transcription initiation. Mutations in several other genes encoding subunits of Mediator have been previously shown to associate with DD/ID, including MED13L, a paralog of MED13. Thus, our findings add MED13 to the group of CDK8-kinase module-associated disease genes. The online version of this article (10.1007/s00439-018-1887-y) contains supplementary material, which is available to authorized users.
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影响因子：
64.8
作者：
Iossifov, Ivan;O'Roak, Brian J.;Sanders, Stephan J.;Ronemus, Michael;Krumm, Niklas;Levy, Dan;Stessman, Holly A.;Witherspoon, Kali T.;Vives, Laura;Patterson, Karynne E.;Smith, Joshua D.;Paeper, Bryan;Nickerson, Deborah A.;Dea, Jeanselle;Dong, Shan;Gonzalez, Luis E.;Mandell, Jeffrey D.;Mane, Shrikant M.;Murtha, Michael T.;Sullivan, Catherine A.;Walker, Michael F.;Waqar, Zainulabedin;Wei, Liping;Willsey, A. Jeremy;Yamrom, Boris;Lee, Yoon-ha;Grabowska, Ewa;Dalkic, Ertugrul;Wang, Zihua;Marks, Steven;Andrews, Peter;Leotta, Anthony;Kendall, Jude;Hakker, Inessa;Rosenbaum, Julie;Ma, Beicong;Rodgers, Linda;Troge, Jennifer;Narzisi, Giuseppe;Yoon, Seungtai;Schatz, Michael C.;Ye, Kenny;McCombie, W. Richard;Shendure, Jay;Eichler, Evan E.;State, Matthew W.;Wigler, Michael
通讯作者：
Wigler, Michael
影响因子：
2
作者：
Boutry-Kryza, Nadia;Labalme, Audrey;Sanlaville, Damien
通讯作者：
Sanlaville, Damien
影响因子：
30.8
作者：
Kircher, Martin;Witten, Daniela M.;Jain, Preti;O'Roak, Brian J.;Cooper, Gregory M.;Shendure, Jay
通讯作者：
Shendure, Jay
影响因子：
14.9
作者：
Drozdetskiy A;Cole C;Procter J;Barton GJ
通讯作者：
Barton GJ
影响因子：
14.9
作者：
Dinkel H;Van Roey K;Michael S;Kumar M;Uyar B;Altenberg B;Milchevskaya V;Schneider M;Kühn H;Behrendt A;Dahl SL;Damerell V;Diebel S;Kalman S;Klein S;Knudsen AC;Mäder C;Merrill S;Staudt A;Thiel V;Welti L;Davey NE;Diella F;Gibson TJ
通讯作者：
Gibson TJ