Opposite Modulation of RAC1 by Mutations in TRIO Is Associated with Distinct, Domain-Specific Neurodevelopmental Disorders
Open accessAbstract
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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De novo missense mutations in TRIO significantly disrupted the exons preceding or containing the RhoGEF domain.
“De novo missense mutations in TRIO significantly disrupted the exons preceding or containing the RhoGEF domain (Figure 5C) 36,37 , and de novo missense mutations in GRIN2A cluster at the base of the ion channel with the most mutations in the exon encoding for the pore of the complex (Figure 5D).”
From Exome sequencing identifies rare coding variants in 10 genes which confer substantial risk for schizophrenia (2020) · cites this paper as [37]
Exome sequencing studies of ASD and severe neurodevelopmental disorders have identified risk genes, with genetic signals concentrated in constrained genes and shared between the two disorders.
“These studies have established that the genetic signals were concentrated in constrained genes and shared between the two disorders35,36.”
From Rare coding variants in ten genes confer substantial risk for schizophrenia (2022) · cites this paper as [36]
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Rare coding variants in ten genes confer substantial risk for schizophrenia
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- Authors
- Barbosa, S., Greville-Heygate, S., Bonnet, M., Godwin, A., Fagotto-Kaufmann, C., Kajava, A. V., Laouteouet, D., Mawby, R., Wai, H. A., Dingemans, A. J. M., Hehir-Kwa, J., Willems, M., Capri, Y., Mehta, S. G., Cox, H., Goudie, D., Vansenne, F., Turnpenny, P., Vincent, M., Cogné, B., Lesca, G., Hertecant, J., Rodriguez, D., Keren, B., Burglen, L., Gérard, M., Putoux, A., Cantagrel, V., Siquier-Pernet, K., Rio, M., Banka, S., Sarkar, A., Steeves, M., Parker, M., Clement, E., Moutton, S., Tran Mau-Them, F., Piton, A., de Vries, B. B. A., Guille, M., Debant, A., Schmidt, S., & Baralle, D.
- Affiliations
- Centre National de la Recherche Scientifique (FR)
- National Health Service (GB)
- University of Portsmouth (GB)
- University of Southampton (GB)
- Radboud University Medical Center (NL)
- Centre Hospitalier Universitaire de Montpellier (FR)
- Cambridge University Hospitals NHS Foundation Trust (GB)
- Ninewells Hospital (GB)
- University Medical Center Groningen (NL)
- Royal Devon & Exeter NHS Foundation Trust (GB)
- Centre Hospitalier Universitaire de Nantes (FR)
- Hospices Civils de Lyon (FR)
- Tawam Hospital (AE)
- Sorbonne Université (FR)
- Pitié-Salpêtrière Hospital (FR)
- Centre Hospitalier Universitaire de Caen Normandie (FR)
- Inserm (FR)
- Hôpital Necker-Enfants Malades (FR)
- University of Manchester (GB)
- Massachusetts General Hospital (US)
- Sheffield Children's NHS Foundation Trust (GB)
- CHU Dijon Bourgogne (FR)
- Institut de génétique et de biologie moléculaire et cellulaire (FR)
- Corresponding author
- Schmidt, Susanne
- Baralle, Diana
- ORCID
- Barbosa, Sónia
- Greville-Heygate, Stephanie
- Bonnet, Maxime
- Godwin, Annie
- Kajava, Andrey V.
- Laouteouet, Damien
- Mawby, Rebecca
- Wai, Htoo Aung
- Dingemans, Alexander J.M.
- Capri, Yline
- Mehta, Sarju G.
- Vansenne, Fleur
- Turnpenny, Peter
- Vincent, Marie
- Cogné, Benjamin
- Lesca, Gaëtan
- Rodriguez, Diana
- Keren, Boris
- Gérard, Marion
- Putoux, Audrey
- Cantagrel, Vincent
- Siquier-Pernet, Karine
- Banka, Siddharth
- Parker, Michael
- Clement, Emma
- Moutton, Sébastien
- Piton, Amélie
- Guille, Matthew
- Debant, Anne
- Schmidt, Susanne
- Baralle, Diana
- Venue
- The American Journal of Human Genetics
- Publisher
- Elsevier BV
- Published
- 2020-03
- Volume
- 106
- Issue
- 3
- Pages
- 338-355
- ISSN
- 0002-9297 (ISSN-L)
- PMC
- PMC7058823
- OpenAlex
- W3008815398
- Cited by
- 104
- References
- 62
- Citations by year
- 2026: 11 · 2025: 22 · 2024: 16 · 2023: 18 · 2022: 15 · 2021: 15 · 2020: 6 · 2019: 1
- FWCI
- 7.92
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- The American Journal of Human Genetics (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (publishedVersion, cc-by)
- ePrints Soton (University of Southampton) (acceptedVersion)
- HAL (submittedVersion, other-oa)
- Discovery Research Portal (University of Dundee) (submittedVersion, cc-by)
- Research Explorer (The University of Manchester) (submittedVersion, other-oa)
- Royal Devon and Exeter Research Repository (Royal Devon and Exeter) (submittedVersion, cc-by)
- Radboud Repository (Radboud University) (submittedVersion)
- Radboud Repository (Radboud University) (submittedVersion, other-oa)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion, cc-by)
- Funders
- Department of Health & Social Care
- Heart of England NHS Foundation Trust
- Cancer Research UK
- Ministère de l'Enseignement supérieur, de la Recherche et de l'Innovation
- Agence Nationale de la Recherche (ANR-10-INBS-04)
- Medical Research Council
- Fondation pour la Recherche Médicale (DEQ20160334942, FRM 2016)
- Biotechnology and Biological Sciences Research Council (BB/R014841/1)
- Ministère de l'Enseignement Supérieur et de la Recherche
- National Institute for Health and Care Research (RP-2016-07-011)
- Wellcome Trust (212942/Z/18/Z)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Keywords
- trios, Rac1, RhoGEF, neurodevelopmental disorders, intellectual disability, autism spectrum disorder, missense mutations, nonsense mutation, spectrin repeats, macrocephaly, microcephaly, developmental delay, Xenopus tropicalis, neuronal migration, actin cytoskeleton
- MeSH terms
- Amino Acid Sequence, Female, Humans, Male, Mutation, Phenotype, Cohort Studies, Protein Serine-Threonine Kinases, Sequence Homology, Amino Acid, Guanine Nucleotide Exchange Factors, rac1 GTP-Binding Protein, HEK293 Cells, Neurodevelopmental Disorders
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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