Activating RAC1 variants in the switch II region cause a developmental syndrome and alter neuronal morphology
Baker, M. J.
Clemente, G. D.
Ansor, N. M.
Hurst, A. C. E.
Jansen, A. C.
Kelly, M. A.
Rudy, N. L.
Xu, Z. L.
Kazanietz, M. G.
Millard, T. H.
AffiliationDivision of Evolution, Infection and Genomics, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester M13 9PL, UK. Manchester Centre For Genomic Medicine, University of Manchester, St Mary's Hospital, Manchester Academic Health Science Centre, Manchester M13 9WL, UK. Division of Developmental Biology & Medicine, Faculty of Biology, Medicine and Health, University of Manchester M13 9PL, UK. Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. Cell Signalling Group, Cancer Research UK Manchester Institute, The University of Manchester, Alderley Park, Macclesfield SK10 4TG, UK. Department of Pediatrics, UZ Brussel, Brussels, Belgium. Neurogenetics Research Group, Vrije Universiteit Brussel, Brussels, Belgium. School of Biochemistry, University of Bristol, Bristol BS8 1TD, UK. Advanced Medical and Dental Institute, Universiti Sains Malaysia, 13200 Kepala Batas, Penang, Malaysia. Columbia University Medical Center, New York 10032, USA. Department of Pediatrics, School of Medicine, Kingston General Hospital, Queen's University, Kingston, ON, Canada. Centre for Medical Genetics, UZ Brussel, Brussels, Belgium. MRC Human Genetics Unit, IGMM, University of Edinburgh, Edinburgh, UK. University of Alabama at Birmingham, Birmingham, Alabama, USA. Pediatric Neurology Unit, Department of Pediatrics, UZ Brussel, Brussels, Belgium. HudsonAlpha Clinical Services Lab, Huntsville, Alabama, USA. Roberts Individualized Medical Genetics Center, Children's Hospital of Philadelphia, Philadelphia, PA, USA. Department of Human Genetics, Inselspital, Bern University Hospital, University of Bern, Switzerland.
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AbstractRAC1 is a highly conserved Rho GTPase critical for several cellular and developmental processes. De novo missense RAC1 variants cause a highly variable neurodevelopmental disorder. Some of these variants have been previously shown to have a dominant negative effect. Most previously reported patients with this disorder have either severe microcephaly or severe macrocephaly. Here we describe eight patients with pathogenic missense RAC1 variants affecting residues between Q61 and R68 within the switch II region of RAC1. These patients display variable combinations of developmental delay, intellectual disability, brain anomalies such as polymicrogyria, and cardiovascular defects with normocephaly or relatively milder micro- or macrocephaly. Pulldown assays, NIH3T3 fibroblasts spreading assays and staining for activated PAK1/2/3 and WAVE2 suggest that these variants increase RAC1 activity and over-activate downstream signalling targets. Axons of neurons isolated from Drosophila embryos expressing the most common of the activating variants are significantly shorter, with an increased density of filopodial protrusions. In vivo, these embryos exhibit frequent defects in axonal organization. Class IV dendritic arborisation neurons expressing this variant exhibit a significant reduction in the total area of the dendritic arbour, increased branching and failure of self-avoidance. RNAi knock down of the WAVE regulatory complex component Cyfip significantly rescues these morphological defects. These results establish that activating substitutions affecting residues Q61-R68 within the switch II region of RAC1 cause developmental syndrome. Our findings reveal that these variants cause altered downstream signalling resulting in abnormal neuronal morphology and reveal the WAVE regulatory complex/Arp2/3 pathway as a possible therapeutic target for activating RAC1 variants. These insights also have the potential to inform the mechanism and therapy for other disorders caused by variants in genes encoding other Rho GTPases, their regulators and downstream effectors.
CitationBanka S, Bennington A, Baker MJ, Rijckmans E, Clemente GD, Ansor NM, et al. Activating RAC1 variants in the switch II region cause a developmental syndrome and alter neuronal morphology [Internet]. Brain. Oxford University Press (OUP); 2022.
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