The first international conference on SYNGAP1-related brain disorders: a stakeholder meeting of families, researchers, clinicians, and regulators
Tóm tắt
Pathologic mutations in SYNGAP1 cause a genetically defined form of intellectual disability (ID) with comorbid epilepsy and autistic features. While only recently discovered, pathogenicity of this gene is a relatively frequent genetic cause of classically undefined developmental delay that progresses to ID with commonly occurring comorbidities. A meeting of 150 people was held that included affected individuals and their caregivers, clinicians that treat this and related brain disorders, neuroscientists that study SYNGAP1 biology or the function of related genes, and representatives from government agencies that fund science and approve new medical treatments. The meeting focused on developing a consensus among all stakeholders as to how best to achieve a more fundamental and profound understanding of SYNGAP1 biology and its role in human disease. From all of these proceedings, several areas of consensus emerged. The clinicians and geneticists agreed that the prevalence of epilepsy and sensory processing impairments in SYNGAP1-related brain disorders approached 100%. The neurobiologists agreed that more basic research is needed to better understand the molecular and cellular functions of the Syngap1 gene, which will lead to targets for therapeutic intervention. Finally, everyone agreed that there is a pressing need to form a robust patient registry as an initial step toward a prospective natural history study of patients with pathogenic SYNGAP1 variants.
Tài liệu tham khảo
Berryer MH, et al. Mutations in SYNGAP1 cause intellectual disability, autism, and a specific form of epilepsy by inducing haploinsufficiency. Hum Mutat. 2013;34(2):385–94.
Mignot C, et al. Genetic and neurodevelopmental spectrum of SYNGAP1-associated intellectual disability and epilepsy. J Med Genet. 2016;53(8):511–22.
Parker MJ, et al. De novo, heterozygous, loss-of-function mutations in SYNGAP1 cause a syndromic form of intellectual disability. Am J Med Genet A. 2015;167A(10):2231–7.
Deciphering Developmental Disorders, S. Large-scale discovery of novel genetic causes of developmental disorders. Nature. 2015;519(7542):223–8.
Deciphering Developmental Disorders, S. Prevalence and architecture of de novo mutations in developmental disorders. Nature. 2017;542(7642):433–8.
De Rubeis S, et al. Synaptic, transcriptional and chromatin genes disrupted in autism. Nature. 2014;515(7526):209–15.
Pinto D, et al. Functional impact of global rare copy number variation in autism spectrum disorders. Nature. 2010;466(7304):368–72.
Iossifov I, et al. The contribution of de novo coding mutations to autism spectrum disorder. Nature. 2014;515(7526):216–21.
O'Roak BJ, et al. Recurrent de novo mutations implicate novel genes underlying simplex autism risk. Nat Commun. 2014;5:5595.
Purcell SM, et al. A polygenic burden of rare disruptive mutations in schizophrenia. Nature. 2014;506(7487):185–90.
Chen HJ, et al. A synaptic Ras-GTPase activating protein (p135 SynGAP) inhibited by CaM kinase II. Neuron. 1998;20(5):895–904.
Kim JH, et al. SynGAP: a synaptic RasGAP that associates with the PSD-95/SAP90 protein family. Neuron. 1998;20(4):683–91.
Komiyama NH, et al. SynGAP regulates ERK/MAPK signaling, synaptic plasticity, and learning in the complex with postsynaptic density 95 and NMDA receptor. J Neurosci. 2002;22(22):9721–32.
Tomoda T, et al. Role of Unc51.1 and its binding partners in CNS axon outgrowth. Genes Dev. 2004;18(5):541–58.
Krapivinsky G, et al. SynGAP-MUPP1-CaMKII synaptic complexes regulate p38 MAP kinase activity and NMDA receptor-dependent synaptic AMPA receptor potentiation. Neuron. 2004;43(4):563–74.
Walkup WGT, et al. Phosphorylation of synaptic GTPase-activating protein (synGAP) by Ca2+/calmodulin-dependent protein kinase II (CaMKII) and cyclin-dependent kinase 5 (CDK5) alters the ratio of its GAP activity toward Ras and Rap GTPases. J Biol Chem. 2015;290(8):4908–27.
Araki Y, et al. Rapid dispersion of SynGAP from synaptic spines triggers AMPA receptor insertion and spine enlargement during LTP. Neuron. 2015;85(1):173–89.
Rumbaugh G, et al. SynGAP regulates synaptic strength and mitogen-activated protein kinases in cultured neurons. Proc Natl Acad Sci U S A. 2006;103(12):4344–51.
Ozkan ED, et al. Reduced cognition in Syngap1 mutants is caused by isolated damage within developing forebrain excitatory neurons. Neuron. 2014;82(6):1317–33.
Aceti M, et al. Syngap1 haploinsufficiency damages a postnatal critical period of pyramidal cell structural maturation linked to cortical circuit assembly. Biol Psychiatry. 2015;77(9):805–15.
Kim JH, et al. The role of synaptic GTPase-activating protein in neuronal development and synaptic plasticity. J Neurosci. 2003;23(4):1119–24.
Clement JP, et al. Pathogenic SYNGAP1 mutations impair cognitive development by disrupting maturation of dendritic spine synapses. Cell. 2012;151(4):709–23.
Guo X, et al. Reduced expression of the NMDA receptor-interacting protein SynGAP causes behavioral abnormalities that model symptoms of schizophrenia. Neuropsychopharmacology. 2009;34(7):1659–72.
Cui Y, et al. Neurofibromin regulation of ERK signaling modulates GABA release and learning. Cell. 2008;135(3):549–60.
Lee YS, et al. Mechanism and treatment for learning and memory deficits in mouse models of Noonan syndrome. Nat Neurosci. 2014;17(12):1736–43.
Han K, et al. SHANK3 overexpression causes manic-like behaviour with unique pharmacogenetic properties. Nature. 2013;503(7474):72–7.
Holder JL Jr, Quach MM. The spectrum of epilepsy and electroencephalographic abnormalities due to SHANK3 loss-of-function mutations. Epilepsia. 2016;57(10):1651–9.
Monteiro P, Feng G. SHANK proteins: roles at the synapse and in autism spectrum disorder. Nat Rev Neurosci. 2017;18(3):147–57.
Bayes A, et al. Characterization of the proteome, diseases and evolution of the human postsynaptic density. Nat Neurosci. 2011;14(1):19–21.
Volk L, et al. Glutamate synapses in human cognitive disorders. Annu Rev Neurosci. 2015;38:127–49.
Wang CC, Held RG, Hall BJ. SynGAP regulates protein synthesis and homeostatic synaptic plasticity in developing cortical networks. PLoS One. 2013;8(12):e83941.
Barnes SA, et al. Convergence of hippocampal pathophysiology in Syngap+/− and Fmr1−/y mice. J Neurosci. 2015;35(45):15073–81.
Richter JD, Bassell GJ, Klann E. Dysregulation and restoration of translational homeostasis in fragile X syndrome. Nat Rev Neurosci. 2015;16(10):595–605.
Huber KM, et al. Dysregulation of mammalian target of rapamycin signaling in mouse models of autism. J Neurosci. 2015;35(41):13836–42.
Hamdan FF, et al. Mutations in SYNGAP1 in autosomal nonsyndromic mental retardation. N Engl J Med. 2009;360(6):599–605.
Hamdan FF, et al. De novo SYNGAP1 mutations in nonsyndromic intellectual disability and autism. Biol Psychiatry. 2011;69(9):898–901.
Carvill GL, et al. Targeted resequencing in epileptic encephalopathies identifies de novo mutations in CHD2 and SYNGAP1. Nat Genet. 2013;45(7):825–30.
Walkup WG, et al. A model for regulation by SynGAP-alpha1 of binding of synaptic proteins to PDZ-domain 'Slots' in the postsynaptic density. Elife. 2016;5. https://doi.org/10.7554/eLife.16813.
Clement JP, et al. SYNGAP1 links the maturation rate of excitatory synapses to the duration of critical-period synaptic plasticity. J Neurosci. 2013;33(25):10447–52.
Ogden KK, Ozkan ED, Rumbaugh G. Prioritizing the development of mouse models for childhood brain disorders. Neuropharmacology. 2016;100:2–16.
Kozol RA, et al. Two knockdown models of the autism genes SYNGAP1 and SHANK3 in zebrafish produce similar behavioral phenotypes associated with embryonic disruptions of brain morphogenesis. Hum Mol Genet. 2015;24(14):4006–23.
Berryer MH, et al. Decrease of SYNGAP1 in GABAergic cells impairs inhibitory synapse connectivity, synaptic inhibition and cognitive function. Nat Commun. 2016;7:13340.