SYNGAP1

SYNGAP1基因
識別號
別名	SYNGAP1；, MRD5, RASA1, RASA5, SYNGAP, synaptic Ras GTPase activating protein 1
外部ID	OMIM：603384 MGI：3039785 HomoloGene：84739 GeneCards：SYNGAP1
相關疾病
	autosomal dominant non-syndromic intellectual disability 5
基因位置（人類）
染色體	6號染色體
終止	33,453,689 bp
基因位置（小鼠）
染色體	小鼠17號染色體
終止	26,972,434 bp
基因本體
分子功能	• GTPase activator activity; • SH3 domain binding;
細胞組分	• 細胞質; • 細胞質基質; • 膜; • intrinsic component of the cytoplasmic side of the plasma membrane; • dendritic shaft; • 突觸後緻密物質; • 細胞膜; • glutamatergic synapse;
生物學過程	• 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; • 訊息傳遞; • 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
	維基資料
檢視/編輯人類	檢視/編輯小鼠

SYNGAP1是在人類中由SYNGAP1 基因編碼的蛋白質。其是由Ras GTPase活化的蛋白質，對於正常的突觸功能與認知能力的發育健全極其重要，其在人體內的突變可能會導致癲癇或智力障礙。^[6]^[7]^[8]

名詞解釋

英文全稱為「Synaptic Ras GTPase-activating protein 1」，也被稱為「synaptic Ras-GAP 1」或者「SynGAP1」。「Synaptic」意為「突觸的」；Ras家族蛋白為一種小GTPase（「-ase」後綴表示酶），廣泛參與細胞分化等過程，其名稱來自「Rat sarcoma（大鼠肉瘤）」的縮寫。「GTPase-activating protein」即GTP酶活化蛋白，簡稱「GAP」，被認為可以控制Ras通路。Ras-GAPs可參與RAS通路調節以及其他途徑的調節，從而參與細胞活動。^[9]本文講述的是Ras-GAPs其中的一種，即SynGAP1。大腦通過突觸建立思維聯繫，異常的突觸Ras-GAP即SynNAP會導致突觸功能缺陷，進而影響記憶與學習，SynGAP1突變被認為許多相關疾病的病因。^[10]

功能

SynGAP1是一個具有多種功能的複雜蛋白質，可能由複雜的亞型以進行短時調節。^[11]其有記錄的功能包含NMDA受體介導的突觸可塑性和AMPA受體通過制止向上游信號傳導通路插入膜的機制。^[12] SynGAP1也與Unc51協同作用於軸突形成中。^[13]SynGAP1是通過抑制Ras信號傳遞影響MAP激酶信號途徑來影響上述過程。^[14]選擇性剪接和多轉錄起點位表現出相反的作用，從而體現了c和n端多功能蛋白質結構域的重要性。例如，SynGAP1的α1端變體的表現會增加突觸強度，而α2c端變體的表現會減少突觸強度。^[11]總體而言，SynGAP1對生物生存與發育不可或缺，敲除該基因後的幼鼠在孕期內或者出生後不久死亡即體現了這一點。^[15]（註：基因決定了所編碼的蛋白質，故敲除基因後蛋白質可能變異而失去作用；本條目中，蛋白質與基因同名，需要區分。）

樹突棘的發展和成熟

SynGAP1分布於後突觸密度區（英語：postsynaptic density）（postsynaptic density,PSD）和興奮性突觸（英語：excitatory synapse）(excitatory synapse)的樹突棘（英語：dendritic spines）(dendritic spines)。基因剔除後得到SynGAP基因雜合子和純合子老鼠，培養其神經，發現樹突棘無論大小均快速成熟，並產生更多的蘑菇狀和相對更細長的刺。^[16] 樹突棘頭部因絲切蛋白（英語：coffin）(Coffin)的磷酸化而增大，這也減少了F-肌動蛋白的切割（severing）和周轉（turnover）。^[17] 樹枝刺的增加大小也對應於結合膜的AMPARs的增加或沉默突觸（英語：Silent synapse）（silent synapse）的的減少。這些神經在微型突觸後興奮電位（英語：EPSP） (mEPSP)中產生更高的頻率和更大的電流。帶有特定蛋白質結構域突變的小鼠模型在新生兒期展現出高度活躍的海馬迴三突觸迴路。突變在第3周的發育中影響最大，而且成年後修復這一突變並不會改善行為和認知水平。^[18]

臨床意義

若干在SYNGAP1基因上的突變被證實為智力障礙的病因之一。而智力障礙有時與由同基因導致的其他缺陷造成的症候群有關，但與SYNGAP1相關的智力障礙並不會出現明顯的症狀，因此稱為無症狀智力障礙（non-syndromic intellectual disability）。這是一個偶發性突變，發生在父母的配子減數分裂或受精過程中，患者的父母往往沒有帶病基因。並且這一突變產生顯性突變基因，因此即使患者只有一個突變的等位基因，最終都將發育為有智力障礙的。^[19]

這種基因突變也被發現與癲癇有關。^[20]

相互作用

SYNGAP1被發現可以與DLG3和ULK1產生相互作用。^[7]^[13]

參考文獻

^ 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.
^ 張紅凱;陳杰. RAS-GTPase活化蛋白在肿瘤发生发展中作用的研究进展. 中國醫學科學院學報: 364-369頁. 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]. （原始內容存檔於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. （原始內容存檔於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] 張紅凱;陳杰. RAS-GTPase活化蛋白在肿瘤发生发展中作用的研究进展. 中國醫學科學院學報: 364-369頁. 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]. （原始內容存檔於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. （原始內容存檔於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.

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