SYNGAP1

Synaptic Ras GTPase activating protein 1
Identifiers
SymbolsSYNGAP1 ; MRD5; RASA1; RASA5; SYNGAP
External IDsOMIM: 603384 MGI: 3039785 HomoloGene: 84739 GeneCards: SYNGAP1 Gene
Orthologs
SpeciesHumanMouse
Entrez8831240057
EnsemblENSG00000197283ENSMUSG00000067629
UniProtQ96PV0F6SEU4
RefSeq (mRNA)NM_001130066NM_001281491
RefSeq (protein)NP_006763NP_001268420
Location (UCSC)Chr 6:
33.39 – 33.42 Mb		Chr 17:
26.94 – 26.97 Mb
PubMed search

Synaptic Ras GTPase-activating protein 1, also known as synaptic Ras-GAP 1 or SYNGAP1, is a protein that in humans is encoded by the SYNGAP1 gene.[1][2][3] SYNGAP1 is a ras GTPase-activating protein that is critical for the development of cognition and proper synapse function. Mutations in humans cause intellectual disability.

Function

SynGAP1 is a complex protein with several functions that may be regulated temporally via complex isoforms.[4] A well documented function of SynGAP1 involves NMDA receptor mediated synaptic plasticity and membrane insertion of AMPA receptors through the suppression of upstream signaling pathways.[5] However, SynGAP1 has also been shown to function cooperatively with Unc51.1 in axon formation.[6] One way SynGAP1 affects these processes is through the MAP kinase signaling pathway by attenuation of Ras signalling.[7] However, alternative splicing and multiple translational start sites have been shown to cause opposing effects, illustrating the importance of multiple functional domains that reside within the c- and n-termini. For example, the expression of an α1 or α2 c-terminal variant of SynGAP1 will either increase or decrease synaptic strength, respectively.[4] Overall, SynGAP1 is essential for development and survival, which is evident as knockout mice die perinatally.[8]

Dendritic spine development and maturation

SynGAP1 is shown to localize at the postsynaptic density on the dendritic spines of excitatory synapses.[2] Cultured neurons of SynGAP heterozygotic and homozygotic knockout mice display accelerated maturation of dendritic spines, including an increase in overall spine size, which produces more mushroom shaped and less stubby spines.[5][7][9] Spine heads are enlarged due to the increased phosphorylation of cofilin, leading to a decrease in F-actin severing and turnover.[10] The increased size of the dendritic spines also corresponded to an increase in membrane bound AMPARs or a decrease in silent synapses. These neurons displayed a higher frequency and larger amplitudes of miniature excitatory postsynaptic potentials (mEPSP).[9] Mice models with domain specific mutations led to neonatal hyperactivity of the hippocampal trisynaptic circuit. Mutations had the greatest impact during the first 3 weeks of development, and reversal of mutations in adults did not improve behavior and cognition.[5]

Clinical significance

Several mutations in the SYNGAP1 gene were identified as the cause of intellectual disability. Intellectual disability is sometimes associated with syndromes of other defects caused by the same gene, but SYNGAP1-associated intellectual disability is not; it is therefore called non-syndromic intellectual disability. Since neither of the parents of children with this condition have the mutation, this means it was a sporadic mutation that occurred during division of the parents' gametes (meiosis) or fertilization of the egg. It is a dominant mutation, which means that the individual will be developmentally disabled even if only one allele is mutated.[11]

Mutations in this gene have also been found associated to cases of epileptic encephalopathies. (doi: 10.1038/ng.2646)

Interactions

SYNGAP1 has been shown to interact with DLG3[2] and ULK1.[6]

References

  1. ↑ "Entrez Gene: SYNGAP1 synaptic Ras GTPase activating protein 1 homolog (rat)".
  2. ↑ 2.0 2.1 2.2 Kim JH, Liao D, Lau LF, Huganir RL (April 1998). "SynGAP: a synaptic RasGAP that associates with the PSD-95/SAP90 protein family". Neuron 20 (4): 683–91. doi:10.1016/S0896-6273(00)81008-9. PMID 9581761.
  3. ↑ Chen HJ, Rojas-Soto M, Oguni A, Kennedy MB (May 1998). "A synaptic Ras-GTPase activating protein (p135 SynGAP) inhibited by CaM kinase II". Neuron 20 (5): 895–904. doi:10.1016/S0896-6273(00)80471-7. PMID 9620694.
  4. ↑ 4.0 4.1 McMahon, AC; Barnett MW, O'Leary TS, Stoney PN, Collins MO, Papadia S, Choudhary JS, Komiyama NH, Grant SGN, Hardingham GE, Wyllie DJA, Kind PC (June 2012). "SynGAP isoforms exert opposing effects on synaptic strength". Nature Communications 3: 900. doi:10.1038/ncomms1900. PMID 22692543.
  5. ↑ 5.0 5.1 5.2 Clement JP, Aceti M, Creson TK, Ozkan E, Shi Y, Reish NJ, Almonte AG, Miller BH, Wiltgen BJ, Miller CA, Xu X, Rumbaugh G (November 2012). "Pathogenic SYNGAP1 Mutations Impair Cognitive Development by Disrupting Maturation of Dendritic Spine Synapses". Cell 151 (4): 709–723. doi:10.1016/j.cell.2012.08.045. PMC 3500766. PMID 23141534.
  6. ↑ 6.0 6.1 Tomoda T, Kim JH, Zhan C, Hatten ME (March 2004). "Role of Unc51.1 and its binding partners in CNS axon outgrowth". Genes Dev. 18 (5): 541–58. doi:10.1101/gad.1151204. PMC 374236. PMID 15014045.
  7. ↑ 7.0 7.1 Rumbaugh G, Adams JP, Kim JH, Huganir RL (March 2006). "SynGAP regulates synaptic strength and mitogen-activated protein kinases in cultured neurons". Proc. Natl. Acad. Sci. U.S.A. 103 (12): 4344–51. doi:10.1073/pnas.0600084103. PMC 1450173. PMID 16537406.
  8. ↑ Kim JH, Lee HK, Takamiya K, Huganir RL (2003). "The role of synaptic GTPase-activating protein in neuronal development and synaptic plasticity". J. Neurosci. 23 (4): 1119–24. PMID 12598599.
  9. ↑ 9.0 9.1 Vazquez, Luis; Chen HJ; Sokolova I; Knuesel I; Kennedy MB (2004). "SynGAP regulates spine formation". J. Neursci. 103 (12): 4344–51. doi:10.1523/jneurosci.3213-04.2004. PMID 15470153.
  10. ↑ Lin, Yu-Chih; Anthony J. Koleske (July 2010). "Mechanisms of synapse and dendrite maintenance and their disruption in psychiatric and neurodegenerative disorders". Annual Review of Neuroscience 33: 349–78. doi:10.1146/annurev-neuro-060909-153204. PMC 3063389. PMID 20367247.
  11. ↑ Hamdan FF, Gauthier J, Spiegelman D, Noreau A, Yang Y, Pellerin S, Dobrzeniecka S, Côté M, Perreault-Linck E, Carmant L, D'Anjou G, Fombonne E, Addington AM, Rapoport JL, Delisi LE, Krebs MO, Mouaffak F, Joober R, Mottron L, Drapeau P, Marineau C, Lafrenière RG, Lacaille JC, Rouleau GA, Michaud JL (February 2009). "Mutations in SYNGAP1 in Autosomal Nonsyndromic Mental Retardation". N. Engl. J. Med. 360 (6): 599–605. doi:10.1056/NEJMoa0805392. PMC 2925262. PMID 19196676.

Further reading

  • Fantl WJ; Escobedo JA; Martin GA et al. (1992). "Distinct phosphotyrosines on a growth factor receptor bind to specific molecules that mediate different signaling pathways". Cell 69 (3): 413–23. doi:10.1016/0092-8674(92)90444-H. PMID 1374684.
  • Kroll J, Waltenberger J (1998). "The vascular endothelial growth factor receptor KDR activates multiple signal transduction pathways in porcine aortic endothelial cells". J. Biol. Chem. 272 (51): 32521–7. doi:10.1074/jbc.272.51.32521. PMID 9405464.
  • Kim JH, Liao D, Lau LF, Huganir RL (1998). "SynGAP: a synaptic RasGAP that associates with the PSD-95/SAP90 protein family". Neuron 20 (4): 683–91. doi:10.1016/S0896-6273(00)81008-9. PMID 9581761.
  • Chen HJ, Rojas-Soto M, Oguni A, Kennedy MB (1998). "A synaptic Ras-GTPase activating protein (p135 SynGAP) inhibited by CaM kinase II". Neuron 20 (5): 895–904. doi:10.1016/S0896-6273(00)80471-7. PMID 9620694.
  • Husi H; Ward MA; Choudhary JS et al. (2000). "Proteomic analysis of NMDA receptor-adhesion protein signaling complexes". Nat. Neurosci. 3 (7): 661–9. doi:10.1038/76615. PMID 10862698.
  • Li W; Okano A; Tian QB et al. (2001). "Characterization of a novel synGAP isoform, synGAP-beta". J. Biol. Chem. 276 (24): 21417–24. doi:10.1074/jbc.M010744200. PMID 11278737.
  • Pei L, Teves RL, Wallace MC, Gurd JW (2001). "Transient cerebral ischemia increases tyrosine phosphorylation of the synaptic RAS-GTPase activating protein, SynGAP". J. Cereb. Blood Flow Metab. 21 (8): 955–63. doi:10.1097/00004647-200108000-00008. PMID 11487731.
  • Nagase T, Kikuno R, Ohara O (2002). "Prediction of the coding sequences of unidentified human genes. XXI. The complete sequences of 60 new cDNA clones from brain which code for large proteins". DNA Res. 8 (4): 179–87. doi:10.1093/dnares/8.4.179. PMID 11572484.
  • Yi J; Kloeker S; Jensen CC et al. (2002). "Members of the Zyxin family of LIM proteins interact with members of the p130Cas family of signal transducers". J. Biol. Chem. 277 (11): 9580–9. doi:10.1074/jbc.M106922200. PMID 11782456.
  • Song B; Meng F; Yan X et al. (2003). "Cerebral ischemia immediately increases serine phosphorylation of the synaptic RAS-GTPase activating protein SynGAP by calcium/calmodulin-dependent protein kinase II alpha in hippocampus of rats". Neurosci. Lett. 349 (3): 183–6. doi:10.1016/S0304-3940(03)00830-9. PMID 12951199.
  • Mungall AJ; Palmer SA; Sims SK et al. (2003). "The DNA sequence and analysis of human chromosome 6". Nature 425 (6960): 805–11. doi:10.1038/nature02055. PMID 14574404.
  • Ota T; Suzuki Y; Nishikawa T et al. (2004). "Complete sequencing and characterization of 21,243 full-length human cDNAs". Nat. Genet. 36 (1): 40–5. doi:10.1038/ng1285. PMID 14702039.
  • Oh JS, Manzerra P, Kennedy MB (2004). "Regulation of the neuron-specific Ras GTPase-activating protein, synGAP, by Ca2+/calmodulin-dependent protein kinase II". J. Biol. Chem. 279 (17): 17980–8. doi:10.1074/jbc.M314109200. PMID 14970204.
  • Tomoda T, Kim JH, Zhan C, Hatten ME (2004). "Role of Unc51.1 and its binding partners in CNS axon outgrowth". Genes Dev. 18 (5): 541–58. doi:10.1101/gad.1151204. PMC 374236. PMID 15014045.
  • Song B, Yan XB, Zhang GY (2004). "PSD-95 promotes CaMKII-catalyzed serine phosphorylation of the synaptic RAS-GTPase activating protein SynGAP after transient brain ischemia in rat hippocampus". Brain Res. 1005 (1–2): 44–50. doi:10.1016/j.brainres.2004.01.032. PMID 15044063.
  • Brandenberger R; Wei H; Zhang S et al. (2005). "Transcriptome characterization elucidates signaling networks that control human ES cell growth and differentiation". Nat. Biotechnol. 22 (6): 707–16. doi:10.1038/nbt971. PMID 15146197.
  • Krapivinsky G; Medina I; Krapivinsky L et al. (2004). "SynGAP-MUPP1-CaMKII synaptic complexes regulate p38 MAP kinase activity and NMDA receptor-dependent synaptic AMPA receptor potentiation". Neuron 43 (4): 563–74. doi:10.1016/j.neuron.2004.08.003. PMID 15312654.
  • Jaffe H, Vinade L, Dosemeci A (2004). "Identification of novel phosphorylation sites on postsynaptic density proteins". Biochem. Biophys. Res. Commun. 321 (1): 210–8. doi:10.1016/j.bbrc.2004.06.122. PMID 15358237.
  • 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. U.S.A 103 (12): 4344–51. doi:10.1073/pnas.0600084103. PMC 1450173. PMID 16537406.