Mutations in SYNGAP1 Cause Intellectual Disability, Autism, and a Specific Form of Epilepsy by Inducing Haploinsufficiency

Human Mutation

Volumn 34, Issue 2, 2013, Pages 385-394

  Berryer, Martin H ^a   Hamdan, Fadi F ^a   Klitten, Laura L ^b,c   Møller, Rikke S ^b,c   Carmant, Lionel ^a   Schwartzentruber, Jeremy ^d   Patry, Lysanne ^a   Dobrzeniecka, Sylvia ^e   Rochefort, Daniel ^e   Neugnot Cerioli, Mathilde ^a   Lacaille, Jean Claude ^a   Niu, Zhiyv ^f   Eng, Christine M ^f   Yang, Yaping ^f   Palardy, Sylvain ^g   Belhumeur, Céline ^g   Rouleau, Guy A ^e   Tommerup, Niels ^c   Immken, Ladonna ^h   Beauchamp, Miriam H ^a   Patel, Gayle Simpson ^h   Majewski, Jacek ^d   Tarnopolsky, Mark A ⁱ   Scheffzek, Klaus ^j   Hjalgrim, Helle ^b,k   Michaud, Jacques L ^a   Di Cristo, Graziella ^a   more..

^a UNIVERSITÉ DE MONTRÉAL   (Canada)

^b DANISH EPILEPSY CENTRE   (Denmark)

^c UNIVERSITY OF COPENHAGEN   (Denmark)

^d MCGILL UNIVERSITY   (Canada)

^e UNIVERSITY OF MONTREAL   (Canada)

^f BAYLOR COLLEGE OF MEDICINE   (United States)

^g UNIVERSITY OF MONTREAL   (Canada)

^h Specially for Children   (United States)

ⁱ MCMASTER UNIVERSITY   (Canada)

^j INNSBRUCK MEDICAL UNIVERSITY   (Austria)

^k UNIVERSITY OF SOUTHERN DENMARK   (Denmark)

more..

Author keywords

Autism; Epilepsy; Haploinsufficiency; Intellectual disability; SYNGAP1

Indexed keywords

ARGININE; MITOGEN ACTIVATED PROTEIN KINASE; PROLINE; PROTEIN; SYNAPTIC RAS GTPASE ACTIVATING PROTEIN 1; UNCLASSIFIED DRUG;

ADOLESCENT; AGED; AMINO ACID SUBSTITUTION; ARTICLE; ATAXIA; AUTISM; CHILD; CLINICAL ARTICLE; CONTROLLED STUDY; DISEASE CONTROL; DISEASE SEVERITY; ELECTROENCEPHALOGRAPHY; ENZYME ACTIVATION; ENZYME ACTIVITY; EXON; FEMALE; GENE DUPLICATION; GENE FREQUENCY; GENE SEQUENCE; GENERALIZED EPILEPSY; HAPLOINSUFFICIENCY; HUMAN; INHERITANCE; INTELLECTUAL IMPAIRMENT; LOSS OF FUNCTION MUTATION; MALE; MISSENSE MUTATION; NONSYNDROMIC INTELLECTUAL DISABILITY; NUCLEOTIDE SEQUENCE; PHENOTYPE; PRESCHOOL CHILD; PRIORITY JOURNAL; PROTEIN DEGRADATION; PROTEIN EXPRESSION; PROTEIN PHOSPHORYLATION; PROTEIN PROTEIN INTERACTION; PYRAMIDAL NERVE CELL; SCHOOL CHILD;

ADOLESCENT; AMINO ACID SEQUENCE; AUTISTIC DISORDER; BLOTTING, WESTERN; CHILD; CHILD, PRESCHOOL; CLONING, MOLECULAR; EPILEPSY; EXOME; EXTRACELLULAR SIGNAL-REGULATED MAP KINASES; FEMALE; HAPLOINSUFFICIENCY; HEK293 CELLS; HUMANS; INTELLECTUAL DISABILITY; MALE; MOLECULAR SEQUENCE DATA; MUTATION, MISSENSE; PHENOTYPE; PHOSPHORYLATION; PROTEIN CONFORMATION; RAS GTPASE-ACTIVATING PROTEINS; SEQUENCE ANALYSIS, DNA; TRANSFECTION;

EID: 84873099026     PISSN: 10597794     EISSN: 10981004     Source Type: Journal    
DOI: 10.1002/humu.22248     Document Type: Article

References (30)

1. Adzhubei IA, Schmidt S, Peshkin L, Ramensky VE, Gerasimova A, Bork P, Kondrashov AS, Sunyaev SR. 2010. A method and server for predicting damaging missense mutations. Nat Methods 7:248-249.
2. Belsham DD, Cai F, Cui H, Smukler SR, Salapatek AM, Shkreta L. 2004. Generation of a phenotypic array of hypothalamic neuronal cell models to study complex neuroendocrine disorders. Endocrinology 145:393-400.
3. Carlisle HJ, Manzerra P, Marcora E, Kennedy MB. 2008. SynGAP regulates steady-state and activity-dependent phosphorylation of cofilin. J Neurosci 28:13673-13683.
4. Chattopadhyaya B, Di Cristo G, Higashiyama H, Knott GW, Kuhlman SJ, Welker E, Huang ZJ. 2004. Experience and activity-dependent maturation of perisomatic GABAergic innervation in primary visual cortex during a postnatal critical period. J Neurosci 24:9598-9611.
5. Chattopadhyaya B, Di Cristo G, Wu CZ, Knott G, Kuhlman S, Fu Y, Palmiter RD, Huang ZJ. 2007. GAD67-mediated GABA synthesis and signaling regulate inhibitory synaptic innervation in the visual cortex. Neuron 54:889-903.
6. Emsley P, Cowtan K. 2004. Coot: model-building tools for molecular graphics. Acta Crystallogr D Biol Crystallogr 60:2126-2132.
7. Fenn TD, Ringe D, Petsko GA. 2003. POVScript+: a program for model and data visualization using persistence of vision ray tracing. J Appl Crystallogr 36:944-947.
8. Guo X, Hamilton PJ, Reish NJ, Sweatt JD, Miller CA, Rumbaugh G. 2009. Reduced expression of the NMDA receptor-interacting protein SynGAP causes behavioral abnormalities that model symptoms of Schizophrenia. Neuropsychopharmacology 34:1659-1672.
9. Hamdan FF, Daoud H, Piton A, Gauthier J, Dobrzeniecka S, Krebs MO, Joober R, Lacaille JC, Nadeau A, Milunsky JM, Wang Z, Carmant L, et al. 2011a. De novo SYNGAP1 mutations in nonsyndromic intellectual disability and autism. Biol Psychiatry 69:898-901.
10. Hamdan FF, Gauthier J, Araki Y, Lin DT, Yoshizawa Y, Higashi K, Park AR, Spiegelman D, Dobrzeniecka S, Piton A, Tomitori H, Daoud H, et al. 2011b. Excess of de novo deleterious mutations in genes associated with glutamatergic systems in nonsyndromic intellectual disability. Am J Hum Genet 88:306-316.
11. Hamdan FF, Gauthier J, Spiegelman D, Noreau A, Yang Y, Pellerin S, Dobrzeniecka S, Cote M, Perreau-Linck E, Carmant L, D'Anjou G, Fombonne E, et al. 2009. Mutations in SYNGAP1 in autosomal nonsyndromic mental retardation. N Engl J Med 360:599-605.
12. Kim JH, Liao D, Lau LF, Huganir RL. 1998. SynGAP: a synaptic RasGAP that associates with the PSD-95/SAP90 protein family. Neuron 20:683-691.
13. Klitten LL, Moller RS, Nikanorova M, Silahtaroglu A, Hjalgrim H, Tommerup N. 2011. A balanced translocation disrupts SYNGAP1 in a patient with intellectual disability, speech impairment, and epilepsy with myoclonic absences (EMA). Epilepsia 52:e190-e193.
14. Komiyama NH, Watabe AM, Carlisle HJ, Porter K, Charlesworth P, Monti J, Strathdee DJ, O'Carroll CM, Martin SJ, Morris RG, O'Dell TJ, Grant SG. 2002. SynGAPregulates ERK/MAPK signaling, synaptic plasticity, and learning in the complex with postsynaptic density 95 and NMDA receptor. J Neurosci 22:9721-9732.
15. Krapivinsky G, Medina I, Krapivinsky L, Gapon S, Clapham DE. 2004. SynGAP-MUPP1-CaMKII synaptic complexes regulate p38 MAP kinase activity and NMDA receptor-dependent synaptic AMPA receptor potentiation. Neuron 43:563-574.
16. Krepischi AC, Rosenberg C, Costa SS, Crolla JA, Huang S, Vianna-Morgante AM. 2010. A novel de novo microdeletion spanning the SYNGAP1 gene on the short arm of chromosome 6 associated with mental retardation. Am J Med Genet A 152A:2376-2378.
17. Kumar P, Henikoff S, Ng PC. 2009. Predicting the effects of coding non-synonymous variants on protein function using the SIFT algorithm. Nat Protoc 4:1073-1081.
18. Li W, Okano A, Tian QB, Nakayama K, Furihata T, Nawa H, Suzuki T. 2001. Characterization of a novel synGAP isoform, synGAP-beta. J Biol Chem 276:21417-21424.
19. Ligeti E, Welti S, Scheffzek K. 2012. Inhibition and termination of physiological responses by GTPase activating proteins. Physiol Rev 92:237-272.
20. Muhia M, Yee BK, Feldon J, Markopoulos F, Knuesel I. 2010. Disruption of hippocampus-regulated behavioural and cognitive processes by heterozygous constitutive deletion of SynGAP. Eur J Neurosci 31:529-543.
21. Opitz-Araya X, Barria A. 2011. Organotypic hippocampal slice cultures. J Vis Exp (48):2462.
22. Pena V, Hothorn M, Eberth A, Kaschau N, Parret A, Gremer L, Bonneau F, Ahmadian MR, Scheffzek K. 2008. The C2 domain of SynGAP is essential for stimulation of the Rap GTPase reaction. EMBO Rep 9:350-355.
23. Pinto D, Pagnamenta AT, Klei L, Anney R, Merico D, Regan R, Conroy J, Magalhaes TR, Correia C, Abrahams BS, Almeida J, Bacchelli E, et al. 2010. Functional impact of global rare copy number variation in autism spectrum disorders. Nature 466:368-372.
24. Qin Y, Zhu Y, Baumgart JP, Stornetta RL, Seidenman K, Mack V, van Aelst L, Zhu JJ. 2005. State-dependent Ras signaling and AMPA receptor trafficking. Genes Dev 19:2000-2015.
25. Rumbaugh G, Adams JP, Kim JH, Huganir RL. 2006. SynGAP regulates synaptic strength and mitogen-activated protein kinases in cultured neurons. Proc Natl Acad Sci USA 103:4344-4351.
26. Scheffzek K, Ahmadian MR, Kabsch W, Wiesmuller L, Lautwein A, Schmitz F, Wittinghofer A. 1997. The Ras-RasGAP complex: structural basis for GTPase activation and its loss in oncogenic Ras mutants. Science 277:333-338.
27. Schwarz JM, Rodelsperger C, Schuelke M, Seelow D. 2010. MutationTaster evaluates disease-causing potential of sequence alterations. Nat Methods 7:575-576.
28. Srour M, Schwartzentruber J, Hamdan FF, Ospina LH, Patry L, Labuda D, Massicotte C, Dobrzeniecka S, Capo-Chichi JM, Papillon-Cavanagh S, Samuels ME, Boycott KM, et al. 2012. Mutations in C5ORF42 cause Joubert syndrome in the French Canadian population. Am J Hum Genet 90:693-700.
29. Vissers LE, de Ligt J, Gilissen C, Janssen I, Steehouwer M, de Vries P, van Lier B, Arts P, Wieskamp N, Del Rosario M, van Bon BW, Hoischen A, et al. 2010. A de novo paradigm for mental retardation. Nat Genet 42:1109-11012.
30. Zollino M, Gurrieri F, Orteschi D, Marangi G, Leuzzi V, Neri G. 2011. Integrated analysis of clinical signs and literature data for the diagnosis and therapy of a previously undescribed 6p21.3 deletion syndrome. Eur J Hum Genet 19:239-242.