在Trio的GEF1域中发现了自闭症谱系障碍相关的从头突变热点。,Nature Communications

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在Trio的GEF1域中发现了自闭症谱系障碍相关的从头突变热点。
Nature Communications ( IF 14.7 ) Pub Date : 2017-09-19 , DOI: 10.1038/s41467-017-00472-0
Anastasiia Sadybekov ₁ , Chen Tian _{2,

3} , Cosimo Arnesano ₄ , Vsevolod Katritch _{1,

2,

4} , Bruce E Herring ₂

Affiliation

Rho鸟嘌呤核苷酸交换因子（RhoGEF）Trio通过直接激活小GTPase Rac1来促进肌动蛋白聚合。最近的研究表明，ASD动物模型中与自闭症谱系障碍（ASD）相关的行为表型可能是由于在谷氨酸能突触中Rac1对肌动蛋白聚合反应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相关的从头突变。我们的研究表明，这些突变在啮齿动物神经元中产生功能低下或功能过高的Trio形式。根据在ASD动物模型中观察到的谷氨酸能神经传递的病理性增加或减少，我们发现这些突变导致突触AMPA受体表达降低或增强了谷氨酸能突触形成。总之，我们的发现暗示了Trio活性的过度和降低以及在ASD相关发病机制中导致的突触功能障碍，并指出谷氨酸能突触的Trio-Rac1途径可能是许多ASD相关基因融合的关键点。 RhoGEF蛋白，可促进肌动蛋白聚合，并参与自闭症谱系障碍（ASD）中的谷氨酸能突触的调节。在此，作者从来自ASD个体的全外显子组测序数据中，在Trio的GEF1域中发现了一大批从头突变，并证实其中一些突变会导致体外谷氨酸能失调。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。。在此，作者从来自ASD个体的全外显子组测序数据中，在Trio的GEF1域中发现了一大批从头突变，并证实其中一些突变会导致体外谷氨酸能失调。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。。在此，作者在来自ASD个体的全外显子组测序数据中，在Trio的GEF1域中发现了一大批从头突变，并证实其中一些突变会导致体外谷氨酸能失调。

"点击查看英文标题和摘要"

An autism spectrum disorder-related de novo mutation hotspot discovered in the GEF1 domain of Trio.

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.

更新日期：2017-09-19

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