Mutations in SYNGAP1 Cause Intellectual Disability,Autism, and a Specific Form of Epilepsy by Inducing Haploinsufficiency |
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| Authors: | Martin H. Berryer Fadi F. Hamdan Laura L. Klitten Rikke S. Møller Lionel Carmant Jeremy Schwartzentruber Lysanne Patry Sylvia Dobrzeniecka Daniel Rochefort Mathilde Neugnot‐Cerioli Jean‐Claude Lacaille Zhiyv Niu Christine M. Eng Yaping Yang Sylvain Palardy Céline Belhumeur Guy A. Rouleau Niels Tommerup LaDonna Immken Miriam H. Beauchamp Gayle Simpson Patel Jacek Majewski Mark A. Tarnopolsky Klaus Scheffzek Helle Hjalgrim Jacques L. Michaud Graziella Di Cristo |
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| Affiliation: | 1. Centre of Excellence in Neurosciences of Université de Montréal and Sainte‐Justine Hospital Research Center, , Montréal, Québec, Canada;2. Danish Epilepsy Centre, , Dianalund, Denmark;3. Wilhelm Johannsen Centre for Functional Genome Research, University of Copenhagen, , Copenhagen, Denmark;4. McGill University and Genome Quebec Innovation Center, , Montréal, Québec, Canada;5. Center of Excellence in Neuroscience of Université de Montréal, Centre de Recherche du Centre Hospitalier de l'Université de Montréal, and Department of Medicine, Université de Montréal, , Montréal, Québec, Canada;6. Groupe de Recherche sur le Système Nerveux Central, Department of Physiology, Université de Montréal, , Montréal, Québec, Canada;7. Department of Molecular and Human Genetics, Baylor College of Medicine, , Houston;8. Department of Psychiatry, Sainte‐Justine Hospital, , Montréal, Québec, Canada;9. Department of Pediatrics, Sainte‐Justine Hospital, , Montréal, Québec, Canada;10. Specially for Children, , Austin, Texas;11. Department of Human Genetics, McGill University, , Montréal, Québec, Canada;12. Medical Sciences, McMaster University, , Hamilton, Ontario, Canada;13. Department of Medicine, McMaster University, , Hamilton, Ontario, Canada;14. Department of Pediatrics, McMaster University, , Hamilton, Ontario, Canada;15. Division of Biological Chemistry, Biocenter, Innsbruck Medical University, , Innsbruck, Austria;16. Institute of Regional Health Services Research, University of Southern Denmark, , Odense, Denmark |
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| Abstract: | De novo mutations in SYNGAP1, which codes for a RAS/RAP GTP‐activating protein, cause nonsyndromic intellectual disability (NSID). All disease‐causing point mutations identified until now in SYNGAP1 are truncating, raising the possibility of an association between this type of mutations and NSID. Here, we report the identification of the first pathogenic missense mutations (c.1084T>C [p.W362R], c.1685C>T [p.P562L]) and three novel truncating mutations (c.283dupC [p.H95PfsX5], c.2212_2213del [p.S738X], and (c.2184del [p.N729TfsX31]) in SYNGAP1 in patients with NSID. A subset of these patients also showed ataxia, autism, and a specific form of generalized epilepsy that can be refractory to treatment. All of these mutations occurred de novo, except c.283dupC, which was inherited from a father who is a mosaic. Biolistic transfection of wild‐type SYNGAP1 in pyramidal cells from cortical organotypic cultures significantly reduced activity‐dependent phosphorylated extracellular signal‐regulated kinase (pERK) levels. In contrast, constructs expressing p.W362R, p.P562L, or the previously described p.R579X had no significant effect on pERK levels. These experiments suggest that the de novo missense mutations, p.R579X, and possibly all the other truncating mutations in SYNGAP1 result in a loss of its function. Moreover, our study confirms the involvement of SYNGAP1 in autism while providing novel insight into the epileptic manifestations associated with its disruption. |
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| Keywords: | SYNGAP1 haploinsufficiency intellectual disability autism epilepsy |
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