ArticleAmerican journal of human genetics2020
Opposite Modulation of RAC1 by Mutations in TRIO Is Associated with Distinct, Domain-Specific Neurodevelopmental Disorders.
Article in American journal of human genetics, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 65 papers.
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Who cites it
65 citing papers in PubMed, 107 citations in OpenAlex.
- Identification and growth features of developmental delay with macrocephaly caused by a novel TRIO variant affecting the second SH3 domain.BMC medical genomics · 2026Article
- Epistasis among clustered lineage-specific amino acid substitutions in the Drosophila Trio protein.PLoS genetics · 2026Article
- Long-read genome sequencing improves detection and functional interpretation of structural and repeat variants in autism.Cell genomics · 2026Article
- Non-coding RNAs (ncRNAs)-mediated high expression of Ras-related C3 botulinum toxin substrate 1 (RAC1) correlates with poor prognosis and tumor immune infiltration of liver hepatocellular carcinoma.Translational cancer research · 2026Article
- Article
- Molecular genotype-phenotype correlation in ACTB- and ACTG1-related non-muscle actinopathies.American journal of human genetics · 2026Article
- Clinical Exome Sequencing as a Key Diagnostic Tool: A Rare de novoMolecular syndromology · 2026Article
- Investigation of Genetic Aetiology in Intellectual Developmental Disorder with Trio-Whole Exome Sequencing Approach.Noro psikiyatri arsivi · 2026Article
- De novo protein-coding gene variants in developmental stuttering.Molecular psychiatry · 2026Article
- De NovoHuman mutation · 2026Article
- The challenge of ultra-rarity: Dual diagnosis of Lafora disease and developmental encephalopathies linked to TRIO and SHANK3 pathogenic variants.Epilepsia open · 2025Article
- Trio and CRMP2 regulate axon branching and Semaphorin3A signaling.Communications biology · 2025Article
- Epistasis among clustered lineage-specific adaptive amino acid substitutions in the Drosophila Trio protein.bioRxiv : the preprint server for biology · 2025Article
- Guanine Nucleotide Exchange Factors and Small GTPases: Their Regulation and Functions, Diseases, and Therapeutic Targets.MedComm · 2025Review
- Oligodendrocyte myelin glycoprotein impairs dendritic arbors via schizophrenia risk gene Trio.Neurobiology of disease · 2025Article
- Inhibition of Rac1 Attenuated Propofol-Induced Neurotoxicity in the Hippocampal Dentate Gyrus in Developing Mice.Neurochemical research · 2025Article
- Unraveling the impact of genetic variants.eLife · 2025Article
- Article
- The Rho GEF Trio functions in contact inhibition of locomotion of neural crest cells by interacting with Ptk7.Development (Cambridge, England) · 2025Article
- Exploring the bidirectional causal relationship between Autism Spectrum Disorder and Schizophrenia using Mendelian randomization.Medicine · 2025Article
5 more citing papers are in PubMed but not listed here.
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Authors and funding
44 authors at 20 institutions in 5 countries.
Funding
Abstract
The Rho-guanine nucleotide exchange factor (RhoGEF) TRIO acts as a key regulator of neuronal migration, axonal outgrowth, axon guidance, and synaptogenesis by activating the GTPase RAC1 and modulating actin cytoskeleton remodeling. Pathogenic variants in TRIO are associated with neurodevelopmental diseases, including intellectual disability (ID) and autism spectrum disorders (ASD). Here, we report the largest international cohort of 24 individuals with confirmed pathogenic missense or nonsense variants in TRIO. The nonsense mutations are spread along the TRIO sequence, and affected individuals show variable neurodevelopmental phenotypes. In contrast, missense variants cluster into two mutational hotspots in the TRIO sequence, one in the seventh spectrin repeat and one in the RAC1-activating GEFD1. Although all individuals in this cohort present with developmental delay and a neuro-behavioral phenotype, individuals with a pathogenic variant in the seventh spectrin repeat have a more severe ID associated with macrocephaly than do most individuals with GEFD1 variants, who display milder ID and microcephaly. Functional studies show that the spectrin and GEFD1 variants cause a TRIO-mediated hyper- or hypo-activation of RAC1, respectively, and we observe a striking correlation between RAC1 activation levels and the head size of the affected individuals. In addition, truncations in TRIO GEFD1 in the vertebrate model X. tropicalis induce defects that are concordant with the human phenotype. This work demonstrates distinct clinical and molecular disorders clustering in the GEFD1 and seventh spectrin repeat domains and highlights the importance of tight control of TRIO-RAC1 signaling in neuronal development.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.