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

Sadybekov, Anastasiia, Tian, Chen, Arnesano, Cosimo, Katritch, Vsevolod, Herring, Bruce E.·2017·Nature Communications
DOI 10.1038/s41467-017-00472-0PMC PMC5605661
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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.

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  • Variants in the genes encoding GTPase-regulating proteins Iqgap1, Iqgap2, Iqsec2, Kalirin, and Trio are associated with epilepsy, autism, schizophrenia, or intellectual disability.

    “where variants in the underlying genes are associated with epilepsy, autism, schizophrenia, or intellectual disability (De Rubeis et al., 2014; Russell et al., 2014; Sadybekov et al., 2017; Shoubridge et al., 2010; Yang et al., 2014”

    From Changes in the Synaptic Proteome in Tauopathy and Rescue of Tau-Induced Synapse Loss by C1q Antibodies (2018) · cites this paper as Sadybekov et al., 2017

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Metadata

Authors
Sadybekov, A., Tian, C., Arnesano, C., Katritch, V., & Herring, B. E.
ORCID
Herring, Bruce E.
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2017-09-19
Volume
8
Issue
1
ISSN
2041-1723
DOI
10.1038/s41467-017-00472-0
PMC
PMC5605661
Cited by
112
References
12
Language
en
Licence

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