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]
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
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]
^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. PMC2925262. PMID19196676.
^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. PMC3704157. PMID23708187.
^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. PMID23161826. S2CID11397001.
^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. PMID30875700. S2CID80619705.
Further reading
Fantl WJ, Escobedo JA, Martin GA, Turck CW, del Rosario M, McCormick F, Williams LT (May 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. PMID1374684. S2CID34434246.
Song B, Meng F, Yan X, Guo J, Zhang G (October 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". Neuroscience Letters. 349 (3): 183–6. doi:10.1016/S0304-3940(03)00830-9. PMID12951199. S2CID19562266.
Song B, Yan XB, Zhang GY (April 2004). "PSD-95 promotes CaMKII-catalyzed serine phosphorylation of the synaptic RAS-GTPase activating protein SynGAP after transient brain ischemia in rat hippocampus". Brain Research. 1005 (1–2): 44–50. doi:10.1016/j.brainres.2004.01.032. PMID15044063. S2CID33854259.
Brandenberger R, Wei H, Zhang S, Lei S, Murage J, Fisk GJ, Li Y, Xu C, Fang R, Guegler K, Rao MS, Mandalam R, Lebkowski J, Stanton LW (June 2004). "Transcriptome characterization elucidates signaling networks that control human ES cell growth and differentiation". Nature Biotechnology. 22 (6): 707–16. doi:10.1038/nbt971. PMID15146197. S2CID27764390.
