Alternative titles; symbols
HGNC Approved Gene Symbol: SYNGAP1
Cytogenetic location: 6p21.32 Genomic coordinates (GRCh38): 6:33,418,167-33,453,689 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 6p21.32 | Intellectual developmental disorder, autosomal dominant 5 | 612621 | Autosomal dominant | 3 |
The SYNGAP1 gene encodes a brain-specific synaptic Ras GTP-ase activating protein that is largely localized to dendritic spines in neocortical pyramidal neurons, where it suppresses signaling pathways linked to NMDA receptor (NMDAR)-mediated synaptic plasticity and AMPA receptor (AMPAR) membrane insertion (summary by Clement et al., 2012 and Berryer et al., 2013).
Calmodulin-dependent protein kinase II (CaMKII; e.g., 114078) is activated in hippocampal neurons by the rise in intracellular calcium that follows stimulation of NMDA receptors (e.g., 138249). CaMKII is concentrated in the postsynaptic density (PSD), a complex of proteins that colocalize with NMDA receptors at synapses. To determine the targets of CaMKII at the postsynaptic site, Chen et al. (1998) sequenced tryptic peptides from rat forebrain PSDs, performed RT-PCR using degenerate primers based on the peptide sequences, and screened a rat brain cDNA library with the PCR products. They isolated cDNAs encoding a novel synaptic Ras-GTPase-activating protein, p135-Syngap, which is a major component of the PSD. The deduced p135-Syngap protein contains a putative pleckstrin homology domain in the N-terminal segment; a region showing partial identity to the C2 domain of p120-RASGAP; a RasGAP motif; a proline-rich, putative SH3 domain-binding site; 29 consensus sites for phosphorylation by CaMKII; and a C-terminal consensus sequence that can bind to the scaffold protein PSD95 (602887). The authors found that p135-Syngap is most highly expressed in the brain, localizes to glutamatergic synapses, and forms a complex with PSD95. Chen et al. (1998) also isolated cDNAs representing alternatively spliced p135-Syngap transcripts, 1 of which encodes a variant p135-Syngap protein lacking the C-terminal consensus site. Oh et al. (2002) corrected the observation of Chen et al. (1998) regarding the activity of p135-SYNGAP and stated that the Ras-GTPase-activating protein is phosphorylated, rather than inhibited, by CaMKII.
The sequence of a human cosmid clone from chromosome 6 that contains the first 2 exons of a human homolog of rat p135-Syngap, named SYNGAP1, has been deposited in GenBank (AL021366).
SYNGAP1 is expressed throughout the forebrain, with particularly high levels in the hippocampus. In mice, Clement et al. (2012) found peak expression of the Syngap1 gene in the hippocampus around postnatal day 14.
Tomoda et al. (2004) found that SynGAP, a negative regulator of Ras (190020), was expressed within axons and growth cones of developing mouse granule cells. Overexpression of SynGAP blocked neurite outgrowth by a mechanism that involved a Ras-like GTPase cascade. Using a yeast 2-hybrid assay, Tomoda et al. (2004) determined that the C terminus of mouse Unc51.1 (603168) bound the C terminus of SynGAP. Both proteins localized to the membrane fraction of mouse cerebral cortex lysates. Using a reporter assay, Tomoda et al. (2004) found that Unc51.1 inhibited SynGAP through its kinase activity. They concluded that Unc51.1 and SynGAP function cooperatively in axon formation.
Rumbaugh et al. (2006) found that SynGAP1 regulated AMPA receptor (AMPAR; see 138248) trafficking, excitatory synaptic transmission, and the number of silent synapses (i.e., excitatory synapses that lack functional AMPARs) in rodent hippocampal and cortical cultured neurons. The results suggested that SynGAP1 affects these characteristics by regulating the MAP kinase (see MAPK1; 176948) signaling pathway.
In 3 of 94 patients with nonsyndromic intellectual developmental disorder-5 (MRD5; 612621), Hamdan et al. (2009) identified 3 different de novo heterozygous truncating mutations in the SYNGAP1 gene (603384.0001-603384.0003). All patients showed global developmental delay with delayed motor development, hypotonia, moderate to severe mental retardation, and severe language impairment without dysmorphic features. Nonpathologic missense variants in the SYNGAP1 gene were identified in 9 of 142 individuals with autism spectrum disorders and 6 of 143 individuals with schizophrenia.
In 3 of 60 patients with nonsyndromic intellectual disability, including 30 with autism spectrum disorder and 9 with epilepsy, Hamdan et al. (2011) identified de novo heterozygous truncating mutations in the SYNGAP1 gene (see, e.g., 603384.0005 and 603384.0006). The children also showed behavioral abnormalities and mood problems. Two had well-controlled epilepsy and acquired microcephaly, and 1 had autism, thus expanding the phenotypic spectrum associated with SYNGAP1 mutations.
Berryer et al. (2013) identified 5 different SYNGAP1 mutations (see, e.g., 603384.0007 and 603384.0008) in 5 unrelated patients with nonsyndromic intellectual disability. There were 3 truncating mutations and 2 missense mutations. These patients were identified by targeted sequencing of the SYNGAP1 gene in several cohorts including a total of 34 patients with nonsyndromic intellectual disability. Of the 5 with mutations, 4 had early-childhood onset of epilepsy, 3 had autism, and 3 had behavioral abnormalities. There were no notable dysmorphic features or structural brain abnormalities. Four of the mutations occurred de novo; 1 was inherited from a mildly affected parent who was mosaic for the mutation. None of the mutant proteins were detected in neuronal cells transfected with the mutations, suggesting decreased stability, even of the missense mutations. Studies in cortical pyramidal neurons showed that the missense mutations were unable to suppress activity-mediated ERK (176872), consistent with a loss of protein function.
Carvill et al. (2013) reported 5 unrelated patients with mental retardation and epileptic encephalopathy associated with heterozygous truncating mutations in the SYNGAP1 gene (see, e.g., 603384.0009-603384.0010). All had delayed development and onset of various seizure types between 6 months and 3 years that were associated with multiple EEG abnormalities and cognitive regression. Four patients had autistic spectrum disorder. In 2 patients, the mutations occurred de novo; in the other 3 patients, DNA from one or both parents was not available for study. Carvill et al. (2013) concluded that epileptic encephalopathy should be part of the phenotypic spectrum associated with SYNGAP1 mutations. These patients were identified from a large cohort of 500 patients with epileptic encephalopathy who underwent targeted sequencing of candidate genes. SYNGAP1 mutations accounted for 1% of cases.
Clement et al. (2012) found that haploinsufficiency for Syngap1 in mice accelerated the maturation of glutamatergic synapses in the hippocampus during the first few weeks of neonatal hippocampal development. Dendritic spines in pyramidal neurons grew larger in the mutant mice compared to wildtype mice during this critical developmental period, and the changes persisted into adulthood. There was a disruption in spine head size, with more mushroom-type spines and fewer stubby spines, the spine motility rates were decreased, and there were spine signaling abnormalities. These changes were accompanied by premature acquisition of functional AMPA receptors in the synapses. Syngap1 haploinsufficiency altered disrupted excitatory/inhibitory balance in the hippocampus, with increased excitation and increased seizure susceptibility. Changes occurred in neural networks that support cognition and behavior, such as the hippocampus, and these effects were linked to lifelong intellectual disability and impaired memory. These studies provided a neurophysiologic mechanism linking abnormal glutamatergic synapse maturation during development to enduring abnormalities in behaviors indicative of neurodevelopmental disorders in humans.
In a female patient with nonsyndromic intellectual developmental disorder (MRD5; 612621), Hamdan et al. (2009) identified a de novo heterozygous 412A-T transversion in the SYNGAP1 gene, resulting in a lys138-to-ter (K138X) substitution.
In a female patient with nonsyndromic intellectual developmental disorder (MRD5; 612621), Hamdan et al. (2009) identified a de novo heterozygous 1735C-T transition in the SYNGAP1 gene, resulting in an arg579-to-ter (R579X) substitution.
In a female patient with nonsyndromic intellectual developmental disorder (MRD5; 612621), Hamdan et al. (2009) identified a de novo heterozygous 1-bp deletion (2438delT) in the SYNGAP1 gene, resulting in a frameshift and premature termination.
In a boy (patient 16) with intellectual developmental disorder with epilepsy, sleep disturbances, no speech, and no dysmorphic features (MRD5; 612621), de Ligt et al. (2012) identified a de novo heterozygous splice site mutation in the SYNGAP1 gene (501-1G-A), likely resulting in exon skipping.
In an 8-month-old girl with intellectual developmental disorder with well-controlled epilepsy and acquired microcephaly (MRD5; 612621), Hamdan et al. (2011) identified a de novo heterozygous 1-bp deletion (2677delC) in the SYNGAP1 gene, resulting in a frameshift and premature termination (Q893Rfs). Brain imaging was normal. The mutation was not found in 380 control individuals. The child also showed behavioral abnormalities and mood problems. She was 1 of 3 patients with a SYNGAP1 mutation identified from a larger cohort of 60 patients with nonsyndromic intellectual disability.
In a 13-year-old boy with intellectual developmental disorder with autistic features (MRD5; 612621), Hamdan et al. (2011) identified a de novo heterozygous G-to-A transition in intron 13 of the SYNGAP1 gene (2294+1G-A) that was shown to cause the skipping of exon 13 and premature termination (Glu706LeufsTer38). The mutation was not found in 380 controls. The child also showed behavioral abnormalities and mood problems. He was 1 of 3 patients with a SYNGAP1 mutation identified from a larger cohort of 60 patients with nonsyndromic intellectual disability, including 30 with autistic spectrum disorders.
In a 3.5-year-old boy of European descent with intellectual developmental disorder with epilepsy and autism (MRD5; 612621), Berryer et al. (2013) identified a de novo heterozygous 1084T-C transition in the SYNGAP1 gene, resulting in a trp362-to-arg (W362R) substitution at a conserved residue in the C2 domain. The mutation was not found in 570 controls or in several large SNP or exome databases. The mutant protein was not detected in neuronal cells transfected with the mutation, suggesting decreased stability. Studies in cortical pyramidal neurons showed that the missense mutation was unable to suppress activity-mediated ERK (176872), consistent with a loss of protein function.
In a 4-year-old girl of European ancestry with intellectual developmental disorder with autism (MRD5; 612621), Berryer et al. (2013) identified a de novo heterozygous 1685C-T transition in the SYNGAP1 gene, resulting in a pro562-to-leu (P562L) substitution at a conserved residue in the GAP domain. Pro562 is located below the presumed RAS/RAP binding groove in a peptide segment connecting 2 alpha-helices, and the substitution may cause steric clashes and destablization of the protein. The mutation was not found in 570 controls or in several large SNP or exome databases. The mutant protein was not detected in neuronal cells transfected with the mutation, suggesting decreased stability. Studies in cortical pyramidal neurons showed that the missense mutation was unable to suppress activity-mediated ERK (176872), consistent with a loss of protein function.
In a 26-year-old woman with intellectual developmental disorder with autistic features and epileptic encephalopathy (MRD5; 612621), Carvill et al. (2013) identified a de novo heterozygous trp257-to-ter mutation in the SYNGAP1 gene. The patient had delayed development, onset of atypical absence seizures at age 3 years, followed by atonic seizures, focal dyscognitive seizures, and myoclonic jerks associated with EEG abnormalities. She showed cognitive regression after seizure onset.
In a 7-year-old girl with intellectual developmental disorder with autistic features and epileptic encephalopathy (MRD5; 612621), Carvill et al. (2013) identified a de novo heterozygous arg143-to-ter (R143X) mutation in the SYNGAP1 gene. The patient had delayed development, onset of absence seizures at age 10 months, and myoclonic jerks associated with EEG abnormalities. She showed cognitive regression after seizure onset.
Berryer, M. H., Hamdan, F. F., Klitten, L. L., Moller, R. S., Carmant, L., Schwartzentruber, J., Patry, L., Dobrzeniecka, S., Rochefort, D., Neugnot-Cerioli, M., Lacaille, J.-C., Niu, Z., and 15 others. Mutations in SYNGAP1 cause intellectual disability, autism, and a specific form of epilepsy by inducing haploinsufficiency. Hum. Mutat. 34: 385-394, 2013. [PubMed: 23161826] [Full Text: https://doi.org/10.1002/humu.22248]
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., Malone, S., Wallace, G., and 22 others. Targeted resequencing in epileptic encephalopathies identifies de novo mutations in CHD2 and SYNGAP1. Nature Genet. 45: 825-830, 2013. [PubMed: 23708187] [Full Text: https://doi.org/10.1038/ng.2646]
Chen, H.-J., Rojas-Soto, M., Oguni, A., Kennedy, M. B. A synaptic Ras-GTPase activating protein (p135 SynGAP) inhibited by CaM kinase II. Neuron 20: 895-904, 1998. Note: Erratum: Neuron 33: 151 only, 2002. [PubMed: 9620694] [Full Text: https://doi.org/10.1016/s0896-6273(00)80471-7]
Clement, J. P., Aceti, M., Creson, T. K., Ozkan, E. D., Shi, Y., Reish, N. J., Almonte, A. G., Miller, B. H., Wiltgen, B. J., Miller, C. A., Xu, X., Rumbaugh, G. Pathogenic SYNGAP1 mutations impair cognitive development by disrupting maturation of dendritic spine synapses. Cell 151: 709-723, 2012. [PubMed: 23141534] [Full Text: https://doi.org/10.1016/j.cell.2012.08.045]
de Ligt, J., Willemsen, M. H., van Bon, B. W. M., Kleefstra, T., Yntema, H. G., Kroes, T., Vulto-van Silfhout, A. T., Koolen, D. A., de Vries, P., Gilissen, C., del Rosario, M., Hoischen, A., Scheffer, H., de Vries, B. B. A., Brunner, H. G., Veltman, J. A., Vissers, L. E. L. M. Diagnostic exome sequencing in persons with severe intellectual disability. New Eng. J. Med. 367: 1921-1929, 2012. [PubMed: 23033978] [Full Text: https://doi.org/10.1056/NEJMoa1206524]
Hamdan, F. F., Daoud, H., Piton, A., Gauthier, J., Dobrzeniecka, S., Krebs, M.-O., Joober, R., Lacaille, J.-C., Nadeau, A., Milunsky, J. M., Wang, Z., Carmant, L., Mottron, L., Beauchamp, M. H., Rouleau, G. A., Michaud, J. L. De novo SYNGAP1 mutations in nonsyndromic intellectual disability and autism. Biol. Psychiat. 69: 898-901, 2011. [PubMed: 21237447] [Full Text: https://doi.org/10.1016/j.biopsych.2010.11.015]
Hamdan, F. F., Gauthier, J., Spiegelman, D., Noreau, A., Yang, Y., Pellerin, S., Dobrzeniecka, S., Cote, M., Perreault-Linck, E., Carmant, L., D'Anjou, G., Fombonne, E., and 13 others. Mutations in SYNGAP1 in autosomal nonsyndromic mental retardation. New Eng. J. Med. 360: 599-605, 2009. Note: Erratum: New Eng. J. Med. 361: 1814 only, 2009. [PubMed: 19196676] [Full Text: https://doi.org/10.1056/NEJMoa0805392]
Oh, J. S., Chen, H.-J., Rojas-Soto, M., Oguni, A., Kennedy, M. B. Erratum. Neuron 33: 151 only, 2002.
Rumbaugh, G., Adams, J. P., Kim, J. H., Huganir, R. L. SynGAP regulates synaptic strength and mitogen-activated protein kinases in cultured neurons. Proc. Nat. Acad. Sci. 103: 4344-4351, 2006. [PubMed: 16537406] [Full Text: https://doi.org/10.1073/pnas.0600084103]
Tomoda, T., Kim, J. H., Zhan, C., Hatten, M. E. Role of Unc51.1 and its binding partners in CNS axon outgrowth. Genes Dev. 18: 541-558, 2004. [PubMed: 15014045] [Full Text: https://doi.org/10.1101/gad.1151204]