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

Nat Commun. 2017 Sep 19;8(1):601. doi: 10.1038/s41467-017-00472-0.

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.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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autism Spectrum Disorder / genetics*
  • Autism Spectrum Disorder / metabolism
  • Autism Spectrum Disorder / physiopathology
  • Female
  • Genetic Predisposition to Disease
  • Glutamic Acid / metabolism
  • Guanine Nucleotide Exchange Factors / genetics*
  • Guanine Nucleotide Exchange Factors / metabolism
  • Humans
  • In Vitro Techniques
  • Male
  • Mutation
  • Nerve Tissue Proteins / genetics*
  • Nerve Tissue Proteins / metabolism
  • Neurons / metabolism*
  • Patch-Clamp Techniques
  • Protein-Serine-Threonine Kinases / genetics*
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, AMPA / metabolism
  • Synapses / metabolism

Substances

  • Guanine Nucleotide Exchange Factors
  • Nerve Tissue Proteins
  • Receptors, AMPA
  • Trio protein, rat
  • Glutamic Acid
  • Protein-Serine-Threonine Kinases
  • TRIO protein, human