SYNGAP1

SYNGAP1基因
识别号
别名	SYNGAP1；, MRD5, RASA1, RASA5, SYNGAP, synaptic Ras GTPase activating protein 1
外部ID	OMIM：603384 MGI：3039785 HomoloGene：84739 GeneCards：SYNGAP1
相关疾病
	autosomal dominant non-syndromic intellectual disability 5
基因位置（人类）
染色体	6号染色体
终止	33,453,689 bp
基因位置（小鼠）
染色体	小鼠17号染色体
终止	26,972,434 bp
基因本体
分子功能	• GTPase activator activity; • SH3 domain binding;
细胞组分	• 细胞质; • 细胞质基质; • 膜; • intrinsic component of the cytoplasmic side of the plasma membrane; • dendritic shaft; • 突触后致密物质; • 细胞膜; • glutamatergic synapse;
生物学过程	• 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; • 信号转导; • Ras protein signal transduction; • negative regulation of Ras protein signal transduction; • maintenance of postsynaptic specialization structure;
	Sources:Amigo / QuickGO
直系同源
	8831
	240057
	ENSG00000227460; ENSG00000197283
	ENSMUSG00000067629
	Q96PV0
	F6SEU4
	NM_006772; NM_001130066
	NM_001281491
	NP_001123538; NP_006763
	NP_001268420; NP_001357962; NP_001357963; NP_001380956
	维基数据
查看/编辑人类	查看/编辑小鼠

SYNGAP1是在人类中由SYNGAP1 基因编码的蛋白质。其是由Ras GTPase激活的蛋白质，对于正常的突触功能与认知能力的发育健全极其重要，其在人体内的突变可能会导致癫痫或智力障碍。^[6]^[7]^[8]

名词解释

英文全称为“Synaptic Ras GTPase-activating protein 1”，也被称为“synaptic Ras-GAP 1”或者“SynGAP1”。“Synaptic”意为“突触的”；Ras家族蛋白为一种小GTPase（“-ase”后缀表示酶），广泛参与细胞分化等过程，其名称来自“Rat sarcoma（大鼠肉瘤）”的缩写。“GTPase-activating protein”即GTP酶激活蛋白，简称“GAP”，被认为可以控制Ras通路。Ras-GAPs可参与RAS通路调节以及其他途径的调节，从而参与细胞活动。^[9]本文讲述的是Ras-GAPs其中的一种，即SynGAP1。大脑通过突触建立思维联系，异常的突触Ras-GAP即SynNAP会导致突触功能缺陷，进而影响记忆与学习，SynGAP1突变被认为许多相关疾病的病因。^[10]

功能

SynGAP1是一个具有多种功能的复杂蛋白质，可能由复杂的亚型以进行短时调节。^[11]其有记录的功能包含NMDA受体介导的突触可塑性和AMPA受体通过制止向上游信号传导通路插入膜的机制。^[12] SynGAP1也与Unc51协同作用于轴突形成中。^[13]SynGAP1是通过抑制Ras信号传递影响MAP激酶信号途径来影响上述过程。^[14]选择性剪接和多转录起点位表现出相反的作用，从而体现了c和n端多功能蛋白质结构域的重要性。例如，SynGAP1的α1端变体的表达会增加突触强度，而α2c端变体的表达会减少突触强度。^[11]总体而言，SynGAP1对生物生存与发育不可或缺，敲除该基因后的幼鼠在孕期内或者出生后不久死亡即体现了这一点。^[15]（注：基因决定了所编码的蛋白质，故敲除基因后蛋白质可能变异而失去作用；本条目中，蛋白质与基因同名，需要区分。）

树突棘的发展和成熟

SynGAP1分布于后突触密度区（英语：postsynaptic density）（postsynaptic density,PSD）和兴奋性突触（英语：excitatory synapse）(excitatory synapse)的树突棘（英语：dendritic spines）(dendritic spines)。基因敲除后得到SynGAP基因杂合子和纯合子老鼠，培养其神经，发现树突棘无论大小均快速成熟，并产生更多的蘑菇状和相对更细长的刺。^[16] 树突棘头部因丝切蛋白（英语：coffin）(Coffin)的磷酸化而增大，这也减少了F-肌动蛋白的切割（severing）和周转（turnover）。^[17] 树枝刺的增加大小也对应于结合膜的AMPARs的增加或沉默突触（英语：Silent synapse）（silent synapse）的的减少。这些神经在微型突触后兴奋电位（英语：EPSP） (mEPSP)中产生更高的频率和更大的电流。带有特定蛋白质结构域突变的小鼠模型在新生儿期展现出高度活跃的海马体三突触回路。突变在第3周的发育中影响最大，而且成年后修复这一突变并不会改善行为和认知水平。^[18]

临床意义

若干在SYNGAP1基因上的突变被证实为智力障碍的病因之一。而智力障碍有时与由同基因导致的其他缺陷造成的综合症有关，但与SYNGAP1相关的智力障碍并不会出现明显的症状，因此称为无症状智力障碍（non-syndromic intellectual disability）。这是一个偶发性突变，发生在父母的配子减数分裂或受精过程中，患者的父母往往没有带病基因。并且这一突变产生显性突变基因，因此即使患者只有一个突变的等位基因，最终都将发育为有智力障碍的。^[19]

这种基因突变也被发现与癫痫有关。^[20]

相互作用

SYNGAP1被发现可以与DLG3和ULK1产生相互作用。^[7]^[13]

参考文献

^ 與SYNGAP1基因相關的疾病；在維基數據上查看/編輯參考.
^ ^2.0 ^2.1 ^2.2 GRCh38: Ensembl release 89: ENSG00000227460、ENSG00000197283 - Ensembl, May 2017
^ ^3.0 ^3.1 ^3.2 GRCm38: Ensembl release 89: ENSMUSG00000067629 - Ensembl, May 2017
^ Human PubMed Reference:. National Center for Biotechnology Information, U.S. National Library of Medicine.
^ Mouse PubMed Reference:. National Center for Biotechnology Information, U.S. National Library of Medicine.
^ Entrez Gene: SYNGAP1 synaptic Ras GTPase activating protein 1 homolog (rat).
^ ^7.0 ^7.1 Kim JH, Liao D, Lau LF, Huganir RL. SynGAP: a synaptic RasGAP that associates with the PSD-95/SAP90 protein family. Neuron. Apr 1998, 20 (4): 683–91. PMID 9581761. doi:10.1016/S0896-6273(00)81008-9.
^ Chen HJ, Rojas-Soto M, Oguni A, Kennedy MB. A synaptic Ras-GTPase activating protein (p135 SynGAP) inhibited by CaM kinase II. Neuron. May 1998, 20 (5): 895–904. PMID 9620694. doi:10.1016/S0896-6273(00)80471-7.
^ 张红凯;陈杰. RAS-GTPase活化蛋白在肿瘤发生发展中作用的研究进展. 中国医学科学院学报: 364-369页. PMID 26149155. doi:10.3881/j.issn.1000-503X.2015.03.024.
^ Neuron：Syngap1基因突变如何导致早期脑损伤 - 组学专区 - 生物谷. news.bioon.com. [2018-01-22]. （原始内容存档于2018-01-23）.
^ ^11.0 ^11.1 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. SynGAP isoforms exert opposing effects on synaptic strength. Nature Communications. June 2012, 3: 900. PMC 3621422  . PMID 22692543. doi:10.1038/ncomms1900.
^ Clement JP, Aceti M, Creson TK, Ozkan ED, Shi Y, Reish NJ, Almonte AG, Miller BH, Wiltgen BJ, Miller CA, Xu X, Rumbaugh G. Pathogenic SYNGAP1 mutations impair cognitive development by disrupting maturation of dendritic spine synapses. Cell. Nov 2012, 151 (4): 709–23. PMC 3500766  . PMID 23141534. doi:10.1016/j.cell.2012.08.045.
^ ^13.0 ^13.1 Tomoda T, Kim JH, Zhan C, Hatten ME. Role of Unc51.1 and its binding partners in CNS axon outgrowth. Genes & Development. Mar 2004, 18 (5): 541–58. PMC 374236  . PMID 15014045. doi:10.1101/gad.1151204.
^ Rumbaugh G, Adams JP, Kim JH, Huganir RL. 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. Mar 2006, 103 (12): 4344–51. PMC 1450173  . PMID 16537406. doi:10.1073/pnas.0600084103.
^ Kim JH, Lee HK, Takamiya K, Huganir RL. The role of synaptic GTPase-activating protein in neuronal development and synaptic plasticity. The Journal of Neuroscience. Feb 2003, 23 (4): 1119–24. PMID 12598599.
^ SynGAP regulates spine formation. The Journal of Neuroscience. Oct 2004, 24 (40): 8862–72. PMID 15470153. doi:10.1523/jneurosci.3213-04.2004.
^ Mechanisms of synapse and dendrite maintenance and their disruption in psychiatric and neurodegenerative disorders. Annual Review of Neuroscience. July 2010, 33: 349–78. PMC 3063389  . PMID 20367247. doi:10.1146/annurev-neuro-060909-153204.
^ Ozkan, Emin D.; Creson, Thomas K.; Kramár, Enikö A.; Rojas, Camilo; Seese, Ron R.; Babyan, Alex H.; Shi, Yulin; Lucero, Rocco; Xu, Xiangmin. Reduced Cognition in Syngap1 Mutants Is Caused by Isolated Damage within Developing Forebrain Excitatory Neurons. Neuron: 1317–1333. [2018-01-22]. doi:10.1016/j.neuron.2014.05.015. （原始内容存档于2018-01-22）.
^ Mutations in SYNGAP1 in autosomal nonsyndromic mental retardation. The New England Journal of Medicine. Feb 2009, 360 (6): 599–605. PMC 2925262  . PMID 19196676. doi:10.1056/NEJMoa0805392.
^ Carvill, Gemma L; Heavin, Sinéad B; Yendle, Simone C; McMahon, Jacinta M; O'Roak, Brian J; Cook, Joseph; Khan, Adiba; Dorschner, Michael O; Weaver, Molly; Calvert, Sophie; Malone, Stephen; Wallace, Geoffrey; Stanley, Thorsten; Bye, Ann M E; Bleasel, Andrew; Howell, Katherine B; Kivity, Sara; Mackay, Mark T; Rodriguez-Casero, Victoria; Webster, Richard; Korczyn, Amos; Afawi, Zaid; Zelnick, Nathanel; Lerman-Sagie, Tally; Lev, Dorit; Møller, Rikke S; Gill, Deepak; Andrade, Danielle M; Freeman, Jeremy L; Sadleir, Lynette G; Shendure, Jay; Berkovic, Samuel F; Scheffer, Ingrid E; Mefford, Heather C. Targeted resequencing in epileptic encephalopathies identifies de novo mutations in CHD2 and SYNGAP1. Nature Genetics. 2013-05-26, 45 (7): 825–830. doi:10.1038/ng.2646.

[1] 與SYNGAP1基因相關的疾病；在維基數據上查看/編輯參考.

[refGRCh38Ensembl-2] 2.0 ^2.1 ^2.2 GRCh38: Ensembl release 89: ENSG00000227460、ENSG00000197283 - Ensembl, May 2017

[refGRCm38Ensembl-3] 3.0 ^3.1 ^3.2 GRCm38: Ensembl release 89: ENSMUSG00000067629 - Ensembl, May 2017

[4] Human PubMed Reference:. National Center for Biotechnology Information, U.S. National Library of Medicine.

[5] Mouse PubMed Reference:. National Center for Biotechnology Information, U.S. National Library of Medicine.

[entrez-6] Entrez Gene: SYNGAP1 synaptic Ras GTPase activating protein 1 homolog (rat).

[pmid9581761-7] 7.0 ^7.1 Kim JH, Liao D, Lau LF, Huganir RL. SynGAP: a synaptic RasGAP that associates with the PSD-95/SAP90 protein family. Neuron. Apr 1998, 20 (4): 683–91. PMID 9581761. doi:10.1016/S0896-6273(00)81008-9.

[pmid9620694-8] Chen HJ, Rojas-Soto M, Oguni A, Kennedy MB. A synaptic Ras-GTPase activating protein (p135 SynGAP) inhibited by CaM kinase II. Neuron. May 1998, 20 (5): 895–904. PMID 9620694. doi:10.1016/S0896-6273(00)80471-7.

[9] 张红凯;陈杰. RAS-GTPase活化蛋白在肿瘤发生发展中作用的研究进展. 中国医学科学院学报: 364-369页. PMID 26149155. doi:10.3881/j.issn.1000-503X.2015.03.024.

[10] Neuron：Syngap1基因突变如何导致早期脑损伤 - 组学专区 - 生物谷. news.bioon.com. [2018-01-22]. （原始内容存档于2018-01-23）.

[McMahon_2012-11] 11.0 ^11.1 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. SynGAP isoforms exert opposing effects on synaptic strength. Nature Communications. June 2012, 3: 900. PMC 3621422  . PMID 22692543. doi:10.1038/ncomms1900.

[Clement_2012-12] Clement JP, Aceti M, Creson TK, Ozkan ED, Shi Y, Reish NJ, Almonte AG, Miller BH, Wiltgen BJ, Miller CA, Xu X, Rumbaugh G. Pathogenic SYNGAP1 mutations impair cognitive development by disrupting maturation of dendritic spine synapses. Cell. Nov 2012, 151 (4): 709–23. PMC 3500766  . PMID 23141534. doi:10.1016/j.cell.2012.08.045.

[pmid15014045-13] 13.0 ^13.1 Tomoda T, Kim JH, Zhan C, Hatten ME. Role of Unc51.1 and its binding partners in CNS axon outgrowth. Genes & Development. Mar 2004, 18 (5): 541–58. PMC 374236  . PMID 15014045. doi:10.1101/gad.1151204.

[pmid16537406-14] Rumbaugh G, Adams JP, Kim JH, Huganir RL. 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. Mar 2006, 103 (12): 4344–51. PMC 1450173  . PMID 16537406. doi:10.1073/pnas.0600084103.

[Kim_2003-15] Kim JH, Lee HK, Takamiya K, Huganir RL. The role of synaptic GTPase-activating protein in neuronal development and synaptic plasticity. The Journal of Neuroscience. Feb 2003, 23 (4): 1119–24. PMID 12598599.

[Vazquez-16] SynGAP regulates spine formation. The Journal of Neuroscience. Oct 2004, 24 (40): 8862–72. PMID 15470153. doi:10.1523/jneurosci.3213-04.2004.

[17] Mechanisms of synapse and dendrite maintenance and their disruption in psychiatric and neurodegenerative disorders. Annual Review of Neuroscience. July 2010, 33: 349–78. PMC 3063389  . PMID 20367247. doi:10.1146/annurev-neuro-060909-153204.

[18] Ozkan, Emin D.; Creson, Thomas K.; Kramár, Enikö A.; Rojas, Camilo; Seese, Ron R.; Babyan, Alex H.; Shi, Yulin; Lucero, Rocco; Xu, Xiangmin. Reduced Cognition in Syngap1 Mutants Is Caused by Isolated Damage within Developing Forebrain Excitatory Neurons. Neuron: 1317–1333. [2018-01-22]. doi:10.1016/j.neuron.2014.05.015. （原始内容存档于2018-01-22）.

[pmid19196676-19] Mutations in SYNGAP1 in autosomal nonsyndromic mental retardation. The New England Journal of Medicine. Feb 2009, 360 (6): 599–605. PMC 2925262  . PMID 19196676. doi:10.1056/NEJMoa0805392.

[20] Carvill, Gemma L; Heavin, Sinéad B; Yendle, Simone C; McMahon, Jacinta M; O'Roak, Brian J; Cook, Joseph; Khan, Adiba; Dorschner, Michael O; Weaver, Molly; Calvert, Sophie; Malone, Stephen; Wallace, Geoffrey; Stanley, Thorsten; Bye, Ann M E; Bleasel, Andrew; Howell, Katherine B; Kivity, Sara; Mackay, Mark T; Rodriguez-Casero, Victoria; Webster, Richard; Korczyn, Amos; Afawi, Zaid; Zelnick, Nathanel; Lerman-Sagie, Tally; Lev, Dorit; Møller, Rikke S; Gill, Deepak; Andrade, Danielle M; Freeman, Jeremy L; Sadleir, Lynette G; Shendure, Jay; Berkovic, Samuel F; Scheffer, Ingrid E; Mefford, Heather C. Targeted resequencing in epileptic encephalopathies identifies de novo mutations in CHD2 and SYNGAP1. Nature Genetics. 2013-05-26, 45 (7): 825–830. doi:10.1038/ng.2646.

[6]

[7]

[8]

[1]

[2]

[3]

[4]

[5]

[9]

[10]

[11]

[12]

[13]

[14]

[15]

[16]

[17]

[18]

[19]

[20]