Mutations in SYNGAP1 Cause Intellectual Disability, Autism, and a Specific Form of Epilepsy by Inducing Haploinsufficiency
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.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
CHD2 and SYNGAP1 are both involved in autosomal-dominant ID, ASD, and epilepsy.
“CHD2 (discussed above) and SYNGAP1 (encoding a Ras/Rap GTP-activating protein) are both involved in autosomal-dominant ID, ASD, and epilepsy.54”
From Convergence of genes and cellular pathways dysregulated in autism spectrum disorders (2014) · cites this paper as [54]
Cites
<i>Coot</i> : model-building tools for molecular graphics
Emsley, P., & Cowtan, K. (2004) · Acta Crystallographica Section D Biological Crystallography · doi:10.1107/s0907444904019158 · Cited by 30,571 · see citing works
A method and server for predicting damaging missense mutations.
Adzhubei, I. A., Schmidt, S., Peshkin, L., Ramensky, V. E., Gerasimova, A., Bork, P., Kondrashov, A. S., & Sunyaev, S. R. (2010) · Nature Methods · doi:10.1038/nmeth0410-248 · Cited by 13,194 · see citing works
Kumar, P., Henikoff, S., & Ng, P. C. (2009) · Nature Protocols · doi:10.1038/nprot.2009.86 · Cited by 6,521 · see citing works
MutationTaster evaluates disease-causing potential of sequence alterations
Schwarz, J. M., Rödelsperger, C., Schuelke, M., & Seelow, D. (2010) · Nature Methods · doi:10.1038/nmeth0810-575 · Cited by 2,975 · see citing works
Functional impact of global rare copy number variation in autism spectrum disorders
Pinto, D., Pagnamenta, A. T., Klei, L., Anney, R., Merico, D., Regan, R., Conroy, J., Magalhaes, T. R., Correia, C., Abrahams, B. S., et al. (2010) · Nature · doi:10.1038/nature09146 · Cited by 2,013 · cited 5× · see citing works
“…SYNGAP1 in patients with ID also supports the concept that SYNGAP1 haploinsufficiency causes ID, even though some of these rearrangements are more difficult to interpret as they involve other genes [Klitten et al., 2011; Krepischi et al., 2010; Pinto et al., 2010; Zollino et al., 2011].”
BackgroundInfluentialThe Ras-RasGAP Complex: Structural Basis for GTPase Activation and Its Loss in Oncogenic Ras Mutants
Scheffzek, K., Ahmadian, M. R., Kabsch, W., Wiesmüller, L., Lautwein, A., Schmitz, F., & Wittinghofer, A. (1997) · Science · doi:10.1126/science.277.5324.333 · Cited by 1,543 · see citing works
Self-citationA de novo paradigm for mental retardation.
Vissers, L. E. L. M., de Ligt, J., Gilissen, C., Janssen, I., Steehouwer, M., de Vries, P., van Lier, B., Arts, P., Wieskamp, N., del Rosario, M., et al. (2010) · Nature Genetics · doi:10.1038/ng.712 · Cited by 852 · see citing works
SynGAP: a Synaptic RasGAP that Associates with the PSD-95/SAP90 Protein Family
Kim, J. H., Liao, D., Lau, L.-F., & Huganir, R. L. (1998) · Neuron · doi:10.1016/s0896-6273(00)81008-9 · Cited by 634 · see citing works
Chattopadhyaya, B., Di Cristo, G., Higashiyama, H., Knott, G. W., Kuhlman, S. J., Welker, E., & Huang, Z. J. (2004) · The Journal of Neuroscience · doi:10.1523/jneurosci.1851-04.2004 · Cited by 596 · see citing works
Self-citationKomiyama, N. H., Watabe, A. M., Carlisle, H. J., Porter, K., Charlesworth, P., Monti, J., Strathdee, D. J. C., O'Carroll, C. M., Martin, S. J., Morris, R. G. M., et al. (2002) · The Journal of Neuroscience · doi:10.1523/jneurosci.22-22-09721.2002 · Cited by 382 · see citing works
Hamdan, F. F., Gauthier, J., Araki, Y., Lin, D.-T., Yoshizawa, Y., Higashi, K., Park, A.-R., Spiegelman, D., Dobrzeniecka, S., Piton, A., et al. (2011) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2011.02.001 · Cited by 349 · see citing works
Mutations in <i>SYNGAP1</i> in Autosomal Nonsyndromic Mental Retardation
Hamdan, F. F., Gauthier, J., Spiegelman, D., Noreau, A., Yang, Y., Pellerin, S., Dobrzeniecka, S., Côté, M., Perreau-Linck, E., Carmant, L., et al. (2009) · New England Journal of Medicine · doi:10.1056/nejmoa0805392 · Cited by 336 · see citing works
Self-citationChattopadhyaya, B., Cristo, G. D., Wu, C. Z., Knott, G. W., Kuhlman, S. J., Fu, Y., Palmiter, R. D., & Huang, Z. J. (2007) · Neuron · doi:10.1016/j.neuron.2007.05.015 · Cited by 326 · see citing works
POVScript+: a program for model and data visualization using persistence of vision ray-tracing
Fenn, T. D., Ringe, D., & Petsko, G. A. (2003) · Journal of Applied Crystallography · doi:10.1107/s0021889803006721 · Cited by 298 · see citing works
Krapivinsky, G., Medina, I., Krapivinsky, L., Gapon, S., & Clapham, D. E. (2004) · Neuron · doi:10.1016/j.neuron.2004.08.003 · Cited by 287 · see citing works
SynGAP regulates synaptic strength and mitogen-activated protein kinases in cultured neurons
Rumbaugh, G., Adams, J. P., Kim, J. H., & Huganir, R. L. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0600084103 · Cited by 260 · see citing works
Belsham, D. D., Cai, F., Cui, H., Smukler, S. R., Salapatek, A. M., & Shkreta, L. (2003) · Endocrinology · doi:10.1210/en.2003-0946 · Cited by 214 · see citing works
De Novo SYNGAP1 Mutations in Nonsyndromic Intellectual Disability and Autism
Hamdan, F. F., Daoud, H., Piton, A., Gauthier, J., Dobrzeniecka, S., Krebs, M.-O., Joober, R., Lacaille, J.-C., Nadeau, A., Milunsky, J. M., et al. (2011) · Biological Psychiatry · doi:10.1016/j.biopsych.2010.11.015 · Cited by 187 · see citing works
Self-citationState-dependent Ras signaling and AMPA receptor traffickingPreprint
Qin, Y., Zhu, Y., Baumgart, J. P., Stornetta, R. L., Seidenman, K. J., Mack, V., Aelst, L. V., & Zhu, J. (2005) · Genes & Development · doi:10.1101/gad.342205 · Cited by 177 · see citing works
Mutations in C5ORF42 Cause Joubert Syndrome in the French Canadian Population
Srour, M., Schwartzentruber, J., Hamdan, F. F., Ospina, L. H., Patry, L., Labuda, D., Massicotte, C., Dobrzeniecka, S., Capo‐Chichi, J., Papillon‐Cavanagh, S., et al. (2012) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2012.02.011 · Cited by 138 · see citing works
Self-citationSynGAP Regulates Steady-State and Activity-Dependent Phosphorylation of Cofilin
Carlisle, H. J., Manzerra, P., Marcora, E., & Kennedy, M. B. (2008) · The Journal of Neuroscience · doi:10.1523/jneurosci.4695-08.2008 · Cited by 128 · see citing works
Guo, X., Hamilton, P. J., Reish, N. J., Sweatt, J. D., Miller, C. A., & Rumbaugh, G. (2009) · Neuropsychopharmacology · doi:10.1038/npp.2008.223 · Cited by 120 · see citing works
The C2 domain of SynGAP is essential for stimulation of the Rap GTPase reaction
Pena, V., Hothorn, M., Eberth, A., Kaschau, N., Parret, A., Gremer, L., Bonneau, F., Ahmadian, M. R., & Scheffzek, K. (2008) · The EMBO Reports · doi:10.1038/embor.2008.20 · Cited by 101 · see citing works
Self-citationMuhia, M., Yee, B. K., Feldon, J., Markopoulos, F., & Knuesel, I. (2010) · European Journal of Neuroscience · doi:10.1111/j.1460-9568.2010.07079.x · Cited by 71 · see citing works
Characterization of a Novel synGAP Isoform, synGAP-β
Li, W., Okano, A., Tian, Q. B., Nakayama, K., Furihata, T., Nawa, H., & Suzuki, T. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m010744200 · Cited by 61 · see citing works
Inhibition and Termination of Physiological Responses by GTPase Activating Proteins
Ligeti, E., Welti, S., & Scheffzek, K. (2012) · Physiological Reviews · doi:10.1152/physrev.00045.2010 · Cited by 51 · see citing works
Self-citationKlitten, L. L., Møller, R. S., Nikanorova, M., Silahtaroglu, A., Hjalgrim, H., & Tommerup, N. (2011) · Epilepsia · doi:10.1111/j.1528-1167.2011.03304.x · Cited by 40 · see citing works
Self-citationZollino, M., Gurrieri, F., Orteschi, D., Marangi, G., Leuzzi, V., & Neri, G. (2010) · European Journal of Human Genetics · doi:10.1038/ejhg.2010.172 · Cited by 37 · see citing works
Krepischi, A. C. V., Rosenberg, C., Costa, S. S., Crolla, J. A., Huang, S., & Vianna‐Morgante, A. M. (2010) · American Journal of Medical Genetics Part A · doi:10.1002/ajmg.a.33554 · Cited by 34 · see citing works
Organotypic Hippocampal Slice Cultures
Opitz-Araya, X., & Barría, A. (2011) · Journal of Visualized Experiments · doi:10.3791/2462-v · Cited by 13 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
A polygenic burden of rare disruptive mutations in schizophrenia
Purcell, S. M., Moran, J. L., Fromer, M., Ruderfer, D., Solovieff, N., Roussos, P., O’Dushlaine, C., Chambert, K., Bergen, S. E., Kähler, A., et al. (2014) · Nature · doi:10.1038/nature12975 · Cited by 1,385 · see citing works
Convergence of genes and cellular pathways dysregulated in autism spectrum disorders
Pinto, D., Delaby, E., Merico, D., Barbosa, M., Merikangas, A., Klei, L., Thiruvahindrapuram, B., Xu, X., Ziman, R., Wang, Z., et al. (2014) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2014.03.018 · Cited by 969 · see citing works
Targeted resequencing in epileptic encephalopathies identifies de novo mutations in CHD2 and SYNGAP1
Carvill, G. L., Heavin, S. B., Yendle, S. C., McMahon, J. M., O'Roak, B. J., Cook, J., Khan, A., Dorschner, M. O., Weaver, M., Calvert, S., et al. (2013) · Nature Genetics · doi:10.1038/ng.2646 · Cited by 687 · see citing works
Self-citationDendritic structural plasticity and neuropsychiatric disease
Forrest, M. P., Parnell, E., & Penzes, P. (2018) · Nature Reviews Neuroscience · doi:10.1038/nrn.2018.16 · Cited by 464 · see citing works
A de novo convergence of autism genetics and molecular neuroscience
Krumm, N., O’Roak, B. J., Shendure, J., & Eichler, E. E. (2014) · Trends in Neurosciences · doi:10.1016/j.tins.2013.11.005 · Cited by 423 · see citing works
Recurrent de novo mutations implicate novel genes underlying simplex autism risk
O'Roak, B. J., Stessman, H. A., Boyle, E. A., Witherspoon, K. T., Martin, B., Lee, C., Vives, L., Baker, C., Hiatt, J. B., Nickerson, D. A., et al. (2014) · Nature Communications · doi:10.1038/ncomms6595 · Cited by 336 · see citing works
Araki, Y., Zeng, M., Zhang, M., & Huganir, R. L. (2015) · Neuron · doi:10.1016/j.neuron.2014.12.023 · Cited by 271 · see citing works
<i>SYNGAP1</i> encephalopathy: A distinctive generalized developmental and epileptic encephalopathy
Vlaskamp, D. R. M., Shaw, B. J., Burgess, R., Mei, D., Montomoli, M., Xie, H., Myers, C. T., Bennett, M. F., XiangWei, W., Williams, D., et al. (2019) · Neurology · doi:10.1212/wnl.0000000000006729 · Cited by 206 · see citing works
Twenty Years of SynGAP Research: From Synapses to Cognition
Gamache, T. R., Araki, Y., & Huganir, R. L. (2020) · The Journal of Neuroscience · doi:10.1523/jneurosci.0420-19.2020 · Cited by 161 · see citing works
Tau exacerbates excitotoxic brain damage in an animal model of stroke
Bi, M., Gladbach, A., van Eersel, J., Ittner, A., Przybyla, M., van Hummel, A., Chua, S. W., van der Hoven, J., Lee, W. S., Müller, J., et al. (2017) · Nature Communications · doi:10.1038/s41467-017-00618-0 · Cited by 167 · see citing works
Aceti, M., Creson, T. K., Vaissiere, T., Rojas, C., Huang, W.-C., Wang, Y.-X., Petralia, R. S., Page, D. T., Miller, C. A., & Rumbaugh, G. (2015) · Biological Psychiatry · doi:10.1016/j.biopsych.2014.08.001 · Cited by 129 · see citing works
Berryer, M. H., Chattopadhyaya, B., Xing, P., Riebe, I., Bosoi, C., Sanon, N., Antoine-Bertrand, J., Lévesque, M., Avoli, M., Hamdan, F. F., et al. (2016) · Nature Communications · doi:10.1038/ncomms13340 · Cited by 93 · see citing works
Self-citationSynGAP regulates synaptic plasticity and cognition independently of its catalytic activity
Araki, Y., Rajkovich, K. E., Gerber, E. E., Gamache, T. R., Johnson, R. C., Tran, T. H. N., Liu, B., Zhu, Q., Hong, I., Kirkwood, A., et al. (2024) · Science · doi:10.1126/science.adk1291 · Cited by 92 · see citing works
Visualizing synaptic plasticity in vivo by large-scale imaging of endogenous AMPA receptors
Graves, A. R., Roth, R. H., Tan, H. L., Zhu, Q., Bygrave, A. M., Lopez-Ortega, E., Hong, I., Spiegel, A. C., Johnson, R. C., Vogelstein, J. T., et al. (2021) · eLife · doi:10.7554/elife.66809 · Cited by 84 · see citing works
Barnes, S. A., Wijetunge, L. S., Jackson, A. D., Katsanevaki, D., Osterweil, E. K., Komiyama, N. H., Grant, S. G. N., Bear, M. F., Nägerl, U. V., Kind, P. C., et al. (2015) · The Journal of Neuroscience · doi:10.1523/jneurosci.1087-15.2015 · Cited by 84 · see citing works
Dendritic spine actin cytoskeleton in autism spectrum disorder
Joensuu, M., Lanoue, V., & Hotulainen, P. (2018) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2017.08.023 · Cited by 65 · see citing works
SYNGAP1 deficiency disrupts synaptic neoteny in xenotransplanted human cortical neurons in vivo
Vermaercke, B., Iwata, R., Wierda, K., Boubakar, L., Rodriguez, P., Ditkowska, M., Bonin, V., & Vanderhaeghen, P. (2024) · Neuron · doi:10.1016/j.neuron.2024.07.007 · Cited by 27 · see citing works
Key roles of C2/GAP domains in SYNGAP1-related pathophysiology
Katsanevaki, D., Till, S. M., Buller-Peralta, I., Nawaz, M. S., Louros, S. R., Kapgal, V., Tiwari, S., Walsh, D., Anstey, N. J., Petrović, N. G., et al. (2024) · Cell Reports · doi:10.1016/j.celrep.2024.114733 · Cited by 22 · see citing works
- Authors
- Berryer, M. H., Hamdan, F. F., Klitten, L. L., Møller, R. S., Carmant, L., Schwartzentruber, J., Patry, L., Dobrzeniecka, S., Rochefort, D., Neugnot-Cerioli, M., Lacaille, J.-C., Niu, Z., Eng, C. M., Yang, Y., Palardy, S., Belhumeur, C., Rouleau, G. A., Tommerup, N., Immken, L., Beauchamp, M. H., Patel, G. S., Majewski, J., Tarnopolsky, M. A., Scheffzek, K., Hjalgrim, H., Michaud, J. L., & Di Cristo, G.
- Affiliations
- CHU Sainte-Justine Research Center (CA)
- University of Copenhagen (DK)
- McGill University and Génome Québec Innovation Centre (CA)
- Centre Hospitalier de l’Université de Montréal (CA)
- Université de Montréal (CA)
- Baylor College of Medicine (US)
- Centre Hospitalier Universitaire Sainte-Justine (CA)
- Specially for Children; Austin; Texas
- McMaster University (CA)
- Innsbruck Medical University (AT)
- University of Southern Denmark (DK)
- Centre of Excellence in Neurosciences of Université de Montréal and Sainte-Justine Hospital Research Center; Montréal; Québec; Canada
- Corresponding author
- Michaud, Jacques L.
- ORCID
- Venue
- Human Mutation
- Publisher
- Hindawi Limited
- Published
- 2012-12-12
- Volume
- 34
- Issue
- 2
- Pages
- 385-394
- ISSN
- 1059-7794 (ISSN-L)
- OpenAlex
- W2023570403
- Cited by
- 266
- References
- 30
- Citations by year
- 2026: 14 · 2025: 22 · 2024: 42 · 2023: 24 · 2022: 22 · 2021: 20 · 2020: 20 · 2019: 18 · 2018: 18 · 2017: 12 · 2016: 21 · 2015: 10 · 2014: 17 · 2013: 5
- FWCI
- 6.17
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Human Mutation (publishedVersion)
- PubMed (publishedVersion)
- University of Southern Denmark Research Portal (University of Southern Denmark) (publishedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (submittedVersion)
- Funders
- Lundbeckfonden (R151-2013-14290, R67-2010-6206)
- Canadian Institutes of Health Research
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Health Sciences › Medicine › Psychiatry and Mental health › Epilepsy research and treatment
- Keywords
- SYNGAP1, non-syndromic intellectual disability, autism spectrum disorder, drug-resistant epilepsy, ataxia, de novo mutations, missense mutations, truncating mutations, haploinsufficiency, ERK1/2 phosphorylation, loss of function
- MeSH terms
- Adolescent, Amino Acid Sequence, Autistic Disorder, Child, Child, Preschool, Cloning, Molecular, Epilepsy, Female, Humans, Male, Intellectual Disability, Molecular Sequence Data, Phenotype, Phosphorylation, Protein Conformation, Transfection, Blotting, Western, Sequence Analysis, DNA, Mutation, Missense, ras GTPase-Activating Proteins, Extracellular Signal-Regulated MAP Kinases, HEK293 Cells, Haploinsufficiency, Exome
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
