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

, Sónia Barbosa, Stephanie Greville-Heygate, Maxime Bonnet, Annie Godwin, Christine Fagotto-Kaufmann, Andrey V. Kajava, Damien Laouteouet, Rebecca Mawby, Htoo Aung Wai, Alexander J. M. Dingemans, Jayne Hehir-Kwa, Marjorlaine Willems, Yline Capri, Sarju G. Mehta, Helen Cox, David Goudie, Fleur Vansenne, Peter Turnpenny, Marie VincentBenjamin Cogné, Gaëtan Lesca, Jozef Hertecant, Diana Rodriguez, Boris Keren, Lydie Burglen, Marion Gérard, Audrey Putoux, Vincent Cantagrel, Karine Siquier-Pernet, Marlene Rio, Siddharth Banka, Ajoy Sarkar, Marcie Steeves, Michael Parker, Emma Clement, Sébastien Moutton, Frédéric Tran Mau-Them, Amélie Piton, Bert B. A. de Vries, Matthew Guille, Anne Debant, Susanne Schmidt, Diana Baralle

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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.

Original languageEnglish
Pages (from-to)338-355
Number of pages18
JournalAmerican Journal of Human Genetics
Volume106
Issue number3
Early online date25 Feb 2020
DOIs
Publication statusPublished - 5 Mar 2020

Keywords

  • autism
  • intellectual disability
  • macrocephaly
  • microcephaly

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    , 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., ... Baralle, D. (2020). Opposite Modulation of RAC1 by Mutations in TRIO Is Associated with Distinct, Domain-Specific Neurodevelopmental Disorders. American Journal of Human Genetics, 106(3), 338-355. https://doi.org/10.1016/j.ajhg.2020.01.018