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Opposite modulation of RAC1 by mutations in TRIO is associated with distinct, domain specific neurodevelopmental disorders

Opposite modulation of RAC1 by mutations in TRIO is associated with distinct, domain specific neurodevelopmental disorders
Opposite modulation of RAC1 by mutations in TRIO is associated with distinct, domain specific neurodevelopmental disorders
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.

autism, intellectual disability, macrocephaly, microcephaly
0002-9297
338-355
Barbosa, Sonia
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Wai, Htoo
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Mehta, Sarju G.
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Vansenne, Fleur
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Turnpenny, Peter
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Vincent, Marie
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Lesca, Gaetan
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Hertecant, Jozef
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Kantagrel, Vincent
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Steeves, Marcie
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Mouttton, Serbastien
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Guille, Matthew
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Schmidt, Susanne
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Baralle, Diana
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Barbosa, Sonia
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Greville-Heygate, Stephanie
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Godwin, Annie
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Fagotto-Kaufmann, Christine
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Kajava, Andrey
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Laouteouet, Damien
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Mawby, Rebecca
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Wai, Htoo
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De Vries, Bert
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Vincent, Marie
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Lesca, Gaetan
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Hertecant, Jozef
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Rodriguez, Diana
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Marion, Gerard
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Putoux, Audrey
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Ramsey, Keri
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Steeves, Marcie
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Parker, Michael
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Clement, Emma
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Mouttton, Serbastien
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Tran-Mau-Them, Frederic
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Piton, Amelie
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Guille, Matthew
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Debant, Anne
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Baralle, Diana
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Barbosa, Sonia, Greville-Heygate, Stephanie, Bonnet, Maxime, Godwin, Annie, Fagotto-Kaufmann, Christine, Kajava, Andrey, Laouteouet, Damien, Mawby, Rebecca, Wai, Htoo, Dingemans, Alexander, De Vries, Bert, Willems, Marjorlaine, Capri, Yline, Mehta, Sarju G., Cox, Helen, Goudie, David, Vansenne, Fleur, Turnpenny, Peter, Vincent, Marie, Lesca, Gaetan, Hertecant, Jozef, Rodriguez, Diana, Marion, Gerard, Putoux, Audrey, Ramsey, Keri, Kantagrel, Vincent, Banka, Sidharth, Sarkar, Ajoy, Steeves, Marcie, Parker, Michael, Clement, Emma, Mouttton, Serbastien, Tran-Mau-Them, Frederic, Piton, Amelie, Guille, Matthew, Debant, Anne, Schmidt, Susanne and Baralle, Diana (2020) Opposite modulation of RAC1 by mutations in TRIO is associated with distinct, domain specific neurodevelopmental disorders. The American Journal of Human Genetics, 106 (3), 338-355. (doi:10.1016/j.ajhg.2020.01.018).

Record type: Article

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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Accepted/In Press date: 27 January 2020
e-pub ahead of print date: 27 February 2020
Published date: 5 March 2020
Keywords: autism, intellectual disability, macrocephaly, microcephaly

Identifiers

Local EPrints ID: 438435
URI: http://eprints.soton.ac.uk/id/eprint/438435
ISSN: 0002-9297
PURE UUID: 56264703-a417-4386-98b0-68bb7be65e19
ORCID for Diana Baralle: ORCID iD orcid.org/0000-0003-3217-4833

Catalogue record

Date deposited: 10 Mar 2020 17:31
Last modified: 26 Nov 2021 02:53

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Contributors

Author: Sonia Barbosa
Author: Stephanie Greville-Heygate
Author: Maxime Bonnet
Author: Annie Godwin
Author: Christine Fagotto-Kaufmann
Author: Andrey Kajava
Author: Damien Laouteouet
Author: Rebecca Mawby
Author: Htoo Wai
Author: Alexander Dingemans
Author: Bert De Vries
Author: Marjorlaine Willems
Author: Yline Capri
Author: Sarju G. Mehta
Author: Helen Cox
Author: David Goudie
Author: Fleur Vansenne
Author: Peter Turnpenny
Author: Marie Vincent
Author: Gaetan Lesca
Author: Jozef Hertecant
Author: Diana Rodriguez
Author: Gerard Marion
Author: Audrey Putoux
Author: Keri Ramsey
Author: Vincent Kantagrel
Author: Sidharth Banka
Author: Ajoy Sarkar
Author: Marcie Steeves
Author: Michael Parker
Author: Emma Clement
Author: Serbastien Mouttton
Author: Frederic Tran-Mau-Them
Author: Amelie Piton
Author: Matthew Guille
Author: Anne Debant
Author: Susanne Schmidt
Author: Diana Baralle ORCID iD

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