Opposite Modulation of RAC1 by Mutations in TRIO Is Associated with Distinct, Domain-Specific Neurodevelopmental Disorders PMID: 32109419

ADC Targets in Oncology

2026-04-10

Opposite Modulation of RAC1 by Mutations in TRIO Is Associated with Distinct, Domain-Specific Neurodevelopmental Disorders

Am J Hum Genet. 2020 Mar 5;106(3):338-355. doi: 10.1016/j.ajhg.2020.01.018.

Sónia Barbosa ¹ , Stephanie Greville-Heygate ² , Maxime Bonnet ¹ , Annie Godwin ³ , Christine Fagotto-Kaufmann ¹ , Andrey V Kajava ¹ , Damien Laouteouet ¹ , Rebecca Mawby ⁴ , Htoo Aung Wai ⁴ , Alexander J M Dingemans ⁵ , Jayne Hehir-Kwa ⁶ , Marjorlaine Willems ⁷ , Yline Capri ⁸ , Sarju G Mehta ⁹ , Helen Cox ¹⁰ , David Goudie ¹¹ , Fleur Vansenne ¹² , Peter Turnpenny ¹³ , Marie Vincent ¹⁴ , Benjamin Cogné ¹⁴ , Gaëtan Lesca ¹⁵ , Jozef Hertecant ¹⁶ , Diana Rodriguez ¹⁷ , Boris Keren ¹⁸ , Lydie Burglen ¹⁹ , Marion Gérard ²⁰ , Audrey Putoux ²¹ , C4RCD Research Group ²² , Vincent Cantagrel ²³ , Karine Siquier-Pernet ²⁴ , Marlene Rio ²⁴ , Siddharth Banka ²⁵ , Ajoy Sarkar ²⁶ , Marcie Steeves ²⁷ , Michael Parker ²⁸ , Emma Clement ²⁹ , Sébastien Moutton ³⁰ , Frédéric Tran Mau-Them ³¹ , Amélie Piton ³² , Bert B A de Vries ⁵ , Matthew Guille ³ , Anne Debant ¹ , Susanne Schmidt ³³ , Diana Baralle ³⁴

Affiliations

1. Centre de Recherche en Biologie Cellulaire de Montpellier, University of Montpellier, Centre National de la Recherche Scientifique 34293 Montpellier, France.
2. Wessex Clinical Genetics, University Hospital Southampton National Health Service Foundation Trust, Southampton SO16 5YA, UK.
3. European Xenopus Resource Centre, School of Biological Sciences, University of Portsmouth, Portsmouth PO1 2DY, UK.
4. Human Development and Health, Faculty of Medicine, University of Southampton, Southampton SO16 6YD, UK.
5. Department of Human Genetics, Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands.
6. Princess Máxima Center for Pediatric Oncology, 3584CS Utrecht, the Netherlands.
7. Département Génétique Médicale, Centre Hospitalier Régional et Universitaire de Montpellier, Montpellier 34295, France.
8. Département de Génétique, Centre Hospitalier Universitaire de Paris, Paris 75019, France.
9. Department of Clinical Genetics, Cambridge University Hospital Trust, Cambridge CB2 0QQ, UK.
10. West Midlands Regional Genetics Service, Birmingham Women's and Children's National Health Service Foundation Trust, Birmingham B15 2TG, UK.
11. Department of Clinical Genetics, Ninewells Hospital, Dundee DD2 1UB, UK.
12. Department of Clinical Genetics, University Medical Center, Groningen 9713 GZ Groningen, the Netherlands.
13. Clinical Genetics Department, Royal Devon and Exeter National Health Service Foundation Trust, Exeter EX1 2ED, UK.
14. Service de Génétique Médicale, Centre Hospitalier Universitaire de Nantes, 44093 Nantes, France.
15. Service de Génétique, Hospices Civils de Lyon, 69002 Lyon, France.
16. Tawam Hospital, PO Box 15258, Al Ain, United Arab Emirates.
17. Service de Neurologie Pédiatrique, Centre de Référence Maladies Rares - Neurogénétique, Sorbonne Université, Assistance Publique-Hôpitaux de Paris, Hôpital Armand Trousseau, 75012 Paris, France.
18. Département de Génétique (Pr Leguern), Hôpital Pitié-Salpêtrière, 75013 Paris, France.
19. Centre de Référence des Malformations et Maladies Congénitales du Cervelet, Département de Génétique et Embryologie Médicale, Hôpital Trousseau, 75012 Paris, France.
20. Service de Génétique, Centre Hospitalier Universitaire de Caen, Caen 14000, France.
21. Service de Génétique, Hospices Civils de Lyon, Bron 69500, France.
22. TGen's Center for Rare Childhood Disorders, Translational Genomics Research Institute, Phoenix, AZ 85012, USA.
23. Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, 75015 Paris, France; Developmental Brain Disorders Laboratory, INSERM UMR 1163, 75015 Paris, France.
24. Developmental Brain Disorders Laboratory, INSERM UMR 1163, 75015 Paris, France; Service de Génétique, Necker Enfants Malades University Hospital, Assistance Publique-Hôpitaux de Pairs, 75015 Paris, France.
25. Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester M13 9WL, UK; Manchester Centre for Genomic Medicine, St Mary's Hospital, Manchester University NHS Foundation Trust, Health Innovation Manchester, Manchester M13 9WL, UK.
26. Department of Clinical Genetics, Nottingham University Hospitals National Health Service Trust, Nottingham NG5 1PB, UK.
27. Mass General Hospital for Children, Boston, MA 02114, USA.
28. Clinical Genetics, Sheffield Children's National Health Service Foundation Trust, Sheffield S10 2TH, UK.
29. Clinical Genetics Department, Great Ormond Street Hospital for Children National Health Service Foundation Trust, London WC1N 3JH, UK.
30. Reference Center for Developmental Anomalies, Department of Medical Genetics, Dijon University Hospital, 21000 Dijon, France.
31. INSERM U1231, Service de Génétique des Anomalies du Développement, Burgundy University, F-21000 Dijon, France.
32. Institut de Génétique et de Biologie Moléculaire et Cellulaire, Strasbourg, University of Strasbourg, 67404 Illkirch, France; Laboratory of Genetic Diagnostic, Hôpitaux Universitaires de Strasbourg, 67091 Strasbourg, France.
33. Centre de Recherche en Biologie Cellulaire de Montpellier, University of Montpellier, Centre National de la Recherche Scientifique 34293 Montpellier, France. Electronic address: [email protected].
34. Wessex Clinical Genetics, University Hospital Southampton National Health Service Foundation Trust, Southampton SO16 5YA, UK; Human Development and Health, Faculty of Medicine, University of Southampton, Southampton SO16 6YD, UK. Electronic address: [email protected].

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.

Keywords

autism; intellectual disability; macrocephaly; microcephaly.