An autism spectrum disorder-related de novo mutation hotspot discovered in the GEF1 domain of Trio.
An autism spectrum disorder-related de novo mutation hotspot discovered in the GEF1 domain of Trio.
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DOI：
10.1038/s41467-017-00472-0
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发表时间：
2017-09-19
影响因子：
16.6
通讯作者：
Herring BE
中科院分区：
文献类型：
--
作者：
Sadybekov A;Tian C;Arnesano C;Katritch V;Herring BE
Rho鸟嘌呤核苷酸交换因子（RhoGEF） Trio通过直接激活小GTPase Rac1促进肌动蛋白聚合。最近的研究表明，自闭症谱系障碍（ASD）动物模型中与ASD相关的行为表型可能是由于Rac1对谷氨酸能突触肌动蛋白聚合的控制失调而产生的。在人类中，我们在Trio的Rac1激活域GEF1中发现了大量与asd相关的新生突变。我们的研究表明，这些突变在体外啮齿动物神经元中产生功能低下或功能亢进的Trio形式。根据在ASD动物模型中观察到的病理谷氨酸能神经传递的增加或减少，我们发现这些突变导致突触AMPA受体表达减少或谷氨酸能突触发生增强。总之，我们的研究结果表明，在asd相关的发病机制中，Trio活性的过度和减少以及由此导致的突触功能障碍，并指出谷氨酸突触上的Trio- rac1通路可能是许多asd相关基因趋同的关键点。Trio是一种RhoGEF蛋白，可促进肌动蛋白聚合，并参与自闭症谱系障碍（ASD）中谷氨酸能突触的调节。作者在ASD个体的全外显子组测序数据中发现了Trio的GEF1结构域的一大簇新生突变，并证实其中一些突变在体外导致谷氨酸能失调。
The Rho guanine nucleotide exchange factor (RhoGEF) Trio promotes actin polymerization by directly activating the small GTPase Rac1. Recent studies suggest that autism spectrum disorder (ASD)-related behavioral phenotypes in animal models of ASD can be produced by dysregulation of Rac1’s control of actin polymerization at glutamatergic synapses. Here, in humans, we discover a large cluster of ASD-related de novo mutations in Trio’s Rac1 activating domain, GEF1. Our study reveals that these mutations produce either hypofunctional or hyperfunctional forms of Trio in rodent neurons in vitro. In accordance with pathological increases or decreases in glutamatergic neurotransmission observed in animal models of ASD, we find that these mutations result in either reduced synaptic AMPA receptor expression or enhanced glutamatergic synaptogenesis. Together, our findings implicate both excessive and reduced Trio activity and the resulting synaptic dysfunction in ASD-related pathogenesis, and point to the Trio-Rac1 pathway at glutamatergic synapses as a possible key point of convergence of many ASD-related genes. Trio is a RhoGEF protein that promotes actin polymerization and is implicated in the regulation of glutamatergic synapses in autism spectrum disorder (ASD). Here the authors identify a large cluster of de novo mutations in the GEF1 domain of Trio in whole-exome sequencing data from individuals with ASD, and confirm that some of these mutations lead to glutamatergic dysregulation in vitro.
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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
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Wigler, Michael
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Gray JA;Shi Y;Usui H;During MJ;Sakimura K;Nicoll RA
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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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