Relevance to Autism

A de novo LoF variant and two de novo missense variants that were predicted to be damaging were observed in ASD probands (PMID 22495306, 22495309, 25363760). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) identified TRIO as a gene meeting high statistical significance with a 0.05 < FDR 0.1, meaning that this gene had a 90% chance of being a true autism gene (PMID 25363760). De novo likely damaging missense variants in this gene have also been identified in patients presenting with intellectual disability (PMID 23033978) and epilepsy (PMID 23934111). An additional de novo likely damaging missense variant in TRIO was identified in an ASD proband from the Autism Genetic Resource Exchange (AGRE) in Stessman et al., 2017. Sadybekov et al., 2017 identified an enrichment of ASD- and NDD-associated missense and loss-of-function (LoF) variants in the GEF1/DH1 subdomain of TRIO; no missense or LoF variants in this domain were observed in 9,937 control exomes. Additional functional analysis of one frameshift variant and three missense variants residing in the Trio GEF1/DH1 subdomain in this report demonstrated effects on Rac1 activation and synaptic function; one of the missense variants that exhibited reduced Rac1 activation and impaired synaptic function, suggestive of a loss-of-function effect, had previously been observed de novo in an ASD proband from the Simons Simplex Collection in Sanders et al., 2012. Barbosa et al., 2020 reported 24 individuals with confirmed pathogenic missense or nonsense variants in the TRIO gene and noted that stereotypy (27%) and autistic behavior (31%) were among the recurrent behavioral phentotypes observed in this cohort; furthermore, the authors found that while all individuals in this cohort presented with developmental delay, individuals with a pathogenic variant in the seventh spectrin repeat (which was shown by functional analysis to cause TRIO-mediated hyper-activation of RAC1) presented with a more severe intellectual disability associated with macrocephaly, whereas individuals with variants in the RAC1-activating GEFD1 domain (which were shown to cause TRIO-mediated hypo-activation of RAC1) presented with milder ID and microcephaly.

Molecular Function

Promotes the exchange of GDP by GTP. Together with leukocyte antigen-related (LAR) protein, it could play a role in coordinating cell-matrix and cytoskeletal rearrangements necessary for cell migration and cell growth.

External Links

References

Model Summary

Mice with selective Trio heterozygous deletion in the dorsal telencephalon through Nex-Cre recombination show decrease in social approach, motor coordination, brain weight and neuron size, apical and basal dendritic length, dendritic branching, and LTP, abnormal synaptic anatomy, function and plasticity, and increased dendritic spine density and increased anxiety in males. Mice with selective Trio homozygous deletion in the dorsal telencephalon through Nex-Cre recombination show increase in syna

References