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SYNGAP1

From Wikipedia, the free encyclopedia
See also: SYNGAP1-related intellectual disability
SYNGAP1
Identifiers
AliasesSYNGAP1, MRD5, RASA1, RASA5, SYNGAP, synaptic Ras GTPase activating protein 1
External IDsOMIM: 603384; MGI: 3039785; HomoloGene: 84739; GeneCards: SYNGAP1; OMA:SYNGAP1 - orthologs
Orthologs
SpeciesHumanMouse
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
NP_001357962
NP_001357963
NP_001380956

Location (UCSC)Chr 6: 33.42 – 33.45 MbChr 17: 26.94 – 26.97 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/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, epilepsy, autism and sensory processing deficits.

Function

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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

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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

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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 developmental and epileptic encephalopathies, autism spectrum disorder, and touch-related sensory processing deficits.[16][17][18]

Epilepsy in this disorder is distinctive, combining eyelid myoclonia with absences and myoclonic-atonic seizures. Seizures are often triggered by eating.[19][20]

Ongoing research

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A causal therapy was the first successful worldwide by the group of Prof. Gerhard Kluger tested at the Schön Klinik in Vogtareuth with statins. In the process, the RAS pathway, which is overactive in SYNGAP1-associated intellectual disability is inhibited by statins. Further clinical studies by the group of Prof. Gerhard Kluger are in preparation.[21]

Interactions

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SYNGAP1 has been shown to interact with DLG3[6] and ULK1.[10]

References

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  1. ^ a b c ENSG00000197283 GRCh38: Ensembl release 89: ENSG00000227460, ENSG00000197283 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000067629 – Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ "Entrez Gene: SYNGAP1 synaptic Ras GTPase activating protein 1 homolog (rat)".
  6. ^ 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. S2CID 12247592.
  7. ^ 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. S2CID 14655729.
  8. ^ a b McMahon AC, Barnett MW, O'Leary TS, Stoney PN, Collins MO, Papadia S, Choudhary JS, Komiyama NH, Grant SG, Hardingham GE, Wyllie DJ, Kind PC (June 2012). "SynGAP isoforms exert opposing effects on synaptic strength". Nature Communications. 3: 900. doi:10.1038/ncomms1900. PMC 3621422. PMID 22692543.
  9. ^ a b c Clement JP, Aceti M, Creson TK, Ozkan ED, 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): 709–23. doi:10.1016/j.cell.2012.08.045. PMC 3500766. PMID 23141534.
  10. ^ 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 & Development. 18 (5): 541–58. doi:10.1101/gad.1151204. PMC 374236. PMID 15014045.
  11. ^ a b Rumbaugh G, Adams JP, Kim JH, Huganir RL (March 2006). "SynGAP regulates synaptic strength and mitogen-activated protein kinases in cultured neurons". Proceedings of the National Academy of Sciences of the United States of America. 103 (12): 4344–51. doi:10.1073/pnas.0600084103. PMC 1450173. PMID 16537406.
  12. ^ Kim JH, Lee HK, Takamiya K, Huganir RL (February 2003). "The role of synaptic GTPase-activating protein in neuronal development and synaptic plasticity". The Journal of Neuroscience. 23 (4): 1119–24. doi:10.1523/JNEUROSCI.23-04-01119.2003. PMC 6742247. PMID 12598599.
  13. ^ a b Vazquez LE, Chen HJ, Sokolova I, Knuesel I, Kennedy MB (October 2004). "SynGAP regulates spine formation". The Journal of Neuroscience. 24 (40): 8862–72. doi:10.1523/jneurosci.3213-04.2004. PMC 6729942. PMID 15470153.
  14. ^ Lin YC, Koleske AJ (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.
  15. ^ Hamdan FF, Gauthier J, Spiegelman D, Noreau A, Yang Y, Pellerin S, Dobrzeniecka S, Côté M, Perreau-Linck E, 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". The New England Journal of Medicine. 360 (6): 599–605. doi:10.1056/NEJMoa0805392. PMC 2925262. PMID 19196676.
  16. ^ Carvill GL, Heavin SB, Yendle SC, McMahon JM, O'Roak BJ, Cook J, Khan A, Dorschner MO, Weaver M, Calvert S, Malone S, Wallace G, Stanley T, Bye AM, Bleasel A, Howell KB, Kivity S, Mackay MT, Rodriguez-Casero V, Webster R, Korczyn A, Afawi Z, Zelnick N, Lerman-Sagie T, Lev D, Møller RS, Gill D, Andrade DM, Freeman JL, Sadleir LG, Shendure J, Berkovic SF, Scheffer IE, Mefford HC (July 2013). "Targeted resequencing in epileptic encephalopathies identifies de novo mutations in CHD2 and SYNGAP1". Nature Genetics. 45 (7): 825–30. doi:10.1038/ng.2646. PMC 3704157. PMID 23708187.
  17. ^ Berryer MH, Hamdan FF, Klitten LL, Møller RS, Carmant L, Schwartzentruber J, et al. (February 2013). "Mutations in SYNGAP1 cause intellectual disability, autism, and a specific form of epilepsy by inducing haploinsufficiency". Human Mutation. 34 (2): 385–94. doi:10.1002/humu.22248. PMID 23161826. S2CID 11397001.
  18. ^ Michaelson SD, Ozkan ED, Aceti M, et al. (December 2018). "SYNGAP1 heterozygosity disrupts sensory processing by reducing touch-related activity within somatosensory cortex circuits". Nature Neuroscience. 21 (12): 1–13. doi:10.1038/s41593-018-0268-0. ISSN 1546-1726. PMC 6309426. PMID 30455457.
  19. ^ Vlaskamp DR, Shaw BJ, Burgess R, Mei D, Montomoli M, Xie H, Myers CT, Bennett MF, XiangWei W, Williams D, Maas SM, Brooks AS, Mancini GM, van de Laar IM, van Hagen JM, Ware TL, Webster RI, Malone S, Berkovic SF, Kalnins RM, Sicca F, Korenke GC, van Ravenswaaij-Arts CM, Hildebrand MS, Mefford HC, Jiang Y, Guerrini R, Scheffer IE (2018-12-12). "SYNGAP1 encephalopathy". Neurology. 92 (2): e96–e107. doi:10.1212/WNL.0000000000006729. ISSN 0028-3878. PMC 6340340. PMID 30541864.
  20. ^ Stülpnagel, Celina von; Hartlieb, Till; Borggräfe, Ingo; et al. (2019-02-01). "Chewing induced reflex seizures ("eating epilepsy") and eye closure sensitivity as a common feature in pediatric patients with SYNGAP1 mutations: Review of literature and report of 8 cases". Seizure: European Journal of Epilepsy. 65: 131–137. doi:10.1016/j.seizure.2018.12.020. ISSN 1059-1311. PMID 30685520.
  21. ^ Kluger G, von Stülpnagel-Steinbeis C, Arnold S, Eschermann K, Hartlieb T (August 2019). "Positive Short-Term Effect of Low-Dose Rosuvastatin in a Patient with SYNGAP1-Associated Epilepsy". Neuropediatrics. 50 (4): 266–267. doi:10.1055/s-0039-1681066. PMID 30875700. S2CID 80619705.

Further reading

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  • Overview of all the structural information available in the PDB for UniProt: F6SEU4 (Mouse Ras/Rap GTPase-activating protein SynGAP) at the PDBe-KB.
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