Haploinsufficiency of autism spectrum disorder candidate gene NUAK1 impairs cortical development and behavior in mice.
Haploinsufficiency of autism spectrum disorder candidate gene NUAK1 impairs cortical development and behavior in mice.
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DOI：
10.1038/s41467-018-06584-5
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发表时间：
2018-10-16
影响因子：
16.6
通讯作者：
Courchet J
中科院分区：
文献类型：
--
作者：
Courchet V;Roberts AJ;Meyer-Dilhet G;Del Carmine P;Lewis TL Jr;Polleux F;Courchet J
最近，在诊断为自闭症谱系障碍（ASD）的患者中发现了许多罕见的新生突变。然而，尽管预测这些从头突变的一些功能丧失的性质，受影响的个人是杂合载体，这将表明，大多数这些候选基因是单倍不足和/或导致显性阴性形式的蛋白质的表达。在这里，我们用候选ASD基因Nuak 1测试了这一假设，我们以前确定了它在皮层连接发展中的作用。我们报告说，Nuak 1是单倍不足的小鼠在皮质发育方面的功能。此外，Nuak 1 +/−小鼠表现出异常行为特征的组合，包括空间记忆巩固缺陷、社会新奇缺陷（但不是社会偏好）和异常感觉运动门控。总的来说，我们的研究结果表明，Nuak 1单倍不足导致皮质连接的发展缺陷和一系列复杂的神经功能缺损。Nuak 1是自闭症谱系障碍的候选基因。在这里，作者报告了Nuak 1杂合子小鼠的行为和皮质发育，表明Nuak 1一个拷贝中的功能缺失突变可能导致神经发育障碍。
Recently, numerous rare de novo mutations have been identified in patients diagnosed with autism spectrum disorders (ASD). However, despite the predicted loss-of-function nature of some of these de novo mutations, the affected individuals are heterozygous carriers, which would suggest that most of these candidate genes are haploinsufficient and/or lead to expression of dominant-negative forms of the protein. Here, we tested this hypothesis with the candidate ASD gene Nuak1 that we previously identified for its role in the development of cortical connectivity. We report that Nuak1 is haploinsufficient in mice with regard to its function in cortical development. Furthermore Nuak1+/− mice show a combination of abnormal behavioral traits ranging from defective spatial memory consolidation, defects in social novelty (but not social preference) and abnormal sensorimotor gating. Overall, our results demonstrate that Nuak1 haploinsufficiency leads to defects in the development of cortical connectivity and a complex array of behavorial deficits. Nuak1 is an autism spectrum disorder candidate gene. Here the authors report behavioral and cortical development in mice heterozygous for Nuak1, suggesting loss of function mutations in one copy of Nuak1 may contribute to neurodevelopmental disorders.
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影响因子：
16.2
作者：
Iossifov I;Ronemus M;Levy D;Wang Z;Hakker I;Rosenbaum J;Yamrom B;Lee YH;Narzisi G;Leotta A;Kendall J;Grabowska E;Ma B;Marks S;Rodgers L;Stepansky A;Troge J;Andrews P;Bekritsky M;Pradhan K;Ghiban E;Kramer M;Parla J;Demeter R;Fulton LL;Fulton RS;Magrini VJ;Ye K;Darnell JC;Darnell RB;Mardis ER;Wilson RK;Schatz MC;McCombie WR;Wigler M
通讯作者：
Wigler M
影响因子：
6.2
作者：
Autism Spectrum Disorders Working Group of The Psychiatric Genomics Consortium
通讯作者：
Autism Spectrum Disorders Working Group of The Psychiatric Genomics Consortium
Neurogenin2调节在callosum中间投射的皮质锥体神经元的初始轴突引导。
影响因子：
3.6
作者：
Hand R;Polleux F
通讯作者：
Polleux F
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：
16.2
作者：
Crump, JG;Zhen, M;Bargmann, CI
通讯作者：
Bargmann, CI