Germline AGO2 mutations impair RNA interference and human neurological development.
Germline AGO2 mutations impair RNA interference and human neurological development.
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种系AGO2突变会损害RNA干扰和人类神经系统发育。
DOI：
10.1038/s41467-020-19572-5
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发表时间：
2020-11-16
影响因子：
16.6
通讯作者：
Kreienkamp HJ
中科院分区：
文献类型：
--
作者：
Lessel D;Zeitler DM;Reijnders MRF;Kazantsev A;Hassani Nia F;Bartholomäus A;Martens V;Bruckmann A;Graus V;McConkie-Rosell A;McDonald M;Lozic B;Tan ES;Gerkes E;Johannsen J;Denecke J;Telegrafi A;Zonneveld-Huijssoon E;Lemmink HH;Cham BWM;Kovacevic T;Ramsdell L;Foss K;Le Duc D;Mitter D;Syrbe S;Merkenschlager A;Sinnema M;Panis B;Lazier J;Osmond M;Hartley T;Mortreux J;Busa T;Missirian C;Prasun P;Lüttgen S;Mannucci I;Lessel I;Schob C;Kindler S;Pappas J;Rabin R;Willemsen M;Gardeitchik T;Löhner K;Rump P;Dias KR;Evans CA;Andrews PI;Roscioli T;Brunner HG;Chijiwa C;Lewis MES;Jamra RA;Dyment DA;Boycott KM;Stegmann APA;Kubisch C;Tan EC;Mirzaa GM;McWalter K;Kleefstra T;Pfundt R;Ignatova Z;Meister G;Kreienkamp HJ
ArgAerte-2和相关的miRNAs形成RNA诱导沉默复合体(RISC)，作为RNA干扰途径的一部分，靶向mRNAs进行翻译沉默和降解。尽管这一过程对细胞功能至关重要，但关于RISC组件在人类发育和器官功能中的作用的信息很少。我们在21名患者中发现了AGO2的13个杂合突变，这些患者受到神经发育障碍的影响。每个已识别的单一氨基酸突变都会导致shRNA介导的沉默受损。我们观察到RISC形成受损或AGO2与mRNA靶标结合增加是突变特有的功能后果。后者由参与mRNA靶向释放的C末端丝氨酸簇的磷酸化减少、神经元中树突状P小体的形成增加以及患者来源的原代成纤维细胞的整体转录组改变而得到支持。我们的数据强调了通过动态AGO2-RNA关联对人类神经元发育进行基因表达调控的重要性。AGO2与miRNAs结合，抑制同源靶mRNAs的表达。在这里，作者报告了AGO2杂合突变导致神经发育缺陷并削弱RNA干扰。
ARGONAUTE-2 and associated miRNAs form the RNA-induced silencing complex (RISC), which targets mRNAs for translational silencing and degradation as part of the RNA interference pathway. Despite the essential nature of this process for cellular function, there is little information on the role of RISC components in human development and organ function. We identify 13 heterozygous mutations in AGO2 in 21 patients affected by disturbances in neurological development. Each of the identified single amino acid mutations result in impaired shRNA-mediated silencing. We observe either impaired RISC formation or increased binding of AGO2 to mRNA targets as mutation specific functional consequences. The latter is supported by decreased phosphorylation of a C-terminal serine cluster involved in mRNA target release, increased formation of dendritic P-bodies in neurons and global transcriptome alterations in patient-derived primary fibroblasts. Our data emphasize the importance of gene expression regulation through the dynamic AGO2-RNA association for human neuronal development. AGO2 binds to miRNAs to repress expression of cognate target mRNAs. Here the authors report that heterozygous AGO2 mutations result in defects in neurological development and impair RNA interference.
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影响因子：
9.2
作者：
Gu, Shuo;Jin, Lan;Huang, Yong;Zhang, Feijie;Kay, Mark A.
通讯作者：
Kay, Mark A.
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影响因子：
33.5
作者：
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通讯作者：
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影响因子：
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作者：
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通讯作者：
Kreienkamp, Hans-Juergen
影响因子：
9.8
作者：
Hempel, Maja;Cremer, Kirsten;Lessel, Davor
通讯作者：
Lessel, Davor
影响因子：
64.8
作者：
Karczewski, Konrad J;Francioli, Laurent C;MacArthur, Daniel G
通讯作者：
MacArthur, Daniel G