SYNGAP1

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Synaptic Ras GTPase activating protein 1
Identifiers
Symbols SYNGAP1 ; MRD5; RASA1; RASA5; SYNGAP
External IDs OMIM603384 MGI3039785 HomoloGene84739 GeneCards: SYNGAP1 Gene
Orthologs
Species Human Mouse
Entrez 8831 240057
Ensembl ENSG00000197283 ENSMUSG00000067629
UniProt Q96PV0 F6SEU4
RefSeq (mRNA) NM_001130066 XM_003085156
RefSeq (protein) NP_006763 XP_003085204
Location (UCSC) Chr 6:
33.39 – 33.42 Mb
Chr 17:
26.94 – 26.97 Mb
PubMed search [1] [2]

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[edit]

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[edit]

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[edit]

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 retarded 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[edit]

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

References[edit]

  1. ^ "Entrez Gene: SYNGAP1 synaptic Ras GTPase activating protein 1 homolog (rat)". 
  2. ^ a b c 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. ^ a b 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. ^ a b c 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. ^ a b 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. ^ a b 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. ^ a b 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[edit]