SYNGAP1

SYNGAP1
Identifiers
Aliases	SYNGAP1, MRD5, RASA1, RASA5, SYNGAP, synaptic Ras GTPase activating protein 1
External IDs	MGI: 3039785 HomoloGene: 84739 GeneCards: SYNGAP1
Gene location (Human) Chr. Chromosome 6 (human)[1] Band No data available Start 33,419,661 bp[1] End 33,457,541 bp[1]
Gene location (Mouse) Chr. Chromosome 17 (mouse)[2] Band No data available Start 26,941,253 bp[2] End 26,972,434 bp[2]
Gene ontology Molecular function • GTPase activator activity • SH3 domain binding Cellular component • cytoplasm • cytosol • membrane • intrinsic component of the cytoplasmic side of the plasma membrane • dendritic shaft • postsynaptic density of dendrite Biological process • pattern specification process • visual learning • negative regulation of neuron apoptotic process • regulation of long-term neuronal synaptic plasticity • regulation of MAPK cascade • regulation of GTPase activity • dendrite development • receptor clustering • MAPK cascade • regulation of synaptic plasticity • positive regulation of GTPase activity • negative regulation of axonogenesis • regulation of synapse structure or activity • signal transduction • negative regulation of Ras protein signal transduction • Ras protein signal transduction Sources:Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	8831	240057
Ensembl	ENSG00000227460 ENSG00000197283	ENSMUSG00000067629
UniProt	Q96PV0	F6SEU4
RefSeq (mRNA)	NM_006772 NM_001130066	NM_001281491
RefSeq (protein)	NP_001123538 NP_006763	NP_001268420
Location (UCSC)	Chr 6: 33.42 – 33.46 Mb	Chr 6: 26.94 – 26.97 Mb
PubMed search	[3]	[4]
Wikidata
View/Edit Human View/Edit Mouse

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.^[5][6][7] SYNGAP1 is a ras GTPase-activating protein that is critical for the development of cognition and proper synapse function. Mutations in humans can cause intellectual disability or epilepsy.

Function

SynGAP1 is a complex protein with several functions that may be regulated temporally via complex isoforms.^[8] 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.^[9] However, SynGAP1 has also been shown to function cooperatively with Unc51.1 in axon formation.^[10] One way SynGAP1 affects these processes is through the MAP kinase signaling pathway by attenuation of Ras signalling.^[11] 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.^[8] Overall, SynGAP1 is essential for development and survival, which is evident as knockout mice die perinatally.^[12]

Dendritic spine development and maturation

SynGAP1 is shown to localize at the postsynaptic density on the dendritic spines of excitatory synapses.^[6] 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.^[9][11][13] Spine heads are enlarged due to the increased phosphorylation of cofilin, leading to a decrease in F-actin severing and turnover.^[14] 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).^[13] 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.^[9]

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.^[15]

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^[6] and ULK1.^[10]

References

Further reading