Abstract

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.

Details

Title
An autism spectrum disorder-related de novo mutation hotspot discovered in the GEF1 domain of Trio
Author
Sadybekov, Anastasiia 1 ; Chen, Tian 2 ; Arnesano, Cosimo 3 ; Katritch, Vsevolod 4 ; Herring, Bruce E 5   VIAFID ORCID Logo 

1  Department of Chemistry, University of Southern California, Los Angeles, CA, USA 
2  Department of Biological Sciences, University of Southern California, Los Angeles, CA, USA; Neuroscience Graduate Program, University of Southern California, Los Angeles, CA, USA 
3  Bridge Institute, University of Southern California, Los Angeles, CA, USA 
4  Department of Chemistry, University of Southern California, Los Angeles, CA, USA; Department of Biological Sciences, University of Southern California, Los Angeles, CA, USA; Bridge Institute, University of Southern California, Los Angeles, CA, USA 
5  Department of Biological Sciences, University of Southern California, Los Angeles, CA, USA 
Pages
1-13
Publication year
2017
Publication date
Sep 2017
Publisher
Nature Publishing Group
e-ISSN
20411723
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41467-017-00472-0
ProQuest document ID
1940508565
Copyright
© 2017. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.