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dc.contributor.authorTurnpenny, Peter
dc.identifier.citationBarbosa S, Greville-Heygate S, Bonnet M, et al. Opposite Modulation of RAC1 by Mutations in TRIO Is Associated with Distinct, Domain-Specific Neurodevelopmental Disorders. Am J Hum Genet. 2020;106(3):338-355. doi:10.1016/j.ajhg.2020.01.018en_US
dc.description.abstractThe 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.en_US
dc.publisherElsevier Scienceen_US
dc.rights© 2020 The Authors. User License Creative Commons Attribution (CC BY 4.0)en_US
dc.rightsCC0 1.0 Universal*
dc.subjectintellectual disabilityen_US
dc.titleOpposite Modulation of RAC1 by Mutations in TRIO Is Associated with Distinct, Domain-Specific Neurodevelopmental Disordersen_US
dc.typeJournal Articleen_US
dc.identifier.journalAmerican Journal of Human Geneticsen_US
dc.description.noteThis article is freely available via Open Access. Click on the publisher URL to access it via the publisher's site.en_US
dc.description.fundingThis work was supported by grants from the Fondation pour la Recherche Médicale (Equipes FRM 2016 , DEQ20160334942 ) to A.D. A PhD fellowship from the Ministère de l’Enseignement Supérieur et de la Recherche supported M.B. The European Xenopus Resource Centre (EXRC) is funded by the Wellcome Trust ( 212942/Z/18/Z ) and the Biotechnology and Biological Sciences Research Council ( BB/R014841/1 ). The Baralle lab is supported by a National Institute for Health Research research professorship to D.B. (RP-2016-07-011). S.G.-H. is funded by a research fellowship from the Health Education England Genomics Education Programme . The DDD study presents independent research commissioned by the Health Innovation Challenge Fund [grant HICF-1009-003 ]. This research was made possible through access to data and findings generated by the 100,000 Genomes Project, which is managed by Genomics England Limited (a wholly owned company of the Department of Health and Social Care). The 100,000 Genomes Project is funded by the National Institute for Health Research and NHS England. The Wellcome Trust, Cancer Research UK, and the Medical Research Council have also funded research infrastructure.en_US
dc.description.admin-notepre-print, post-print (6 month embargo)en_US

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