Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT41HVYQ)

• DOT Name: Ras/Rap GTPase-activating protein SynGAP (SYNGAP1)
• Synonyms: Neuronal RasGAP; Synaptic Ras GTPase-activating protein 1; Synaptic Ras-GAP 1
• Gene Name: SYNGAP1
• Related Disease:
  Blepharospasm
  Cognitive impairment
  Complex neurodevelopmental disorder
  Intellectual disability, autosomal dominant 5
  Nervous system disease
  Brain disease
  Capillary malformation-arteriovenous malformation syndrome
  Dowling-Degos disease
  Epilepsy
  Epilepsy, idiopathic generalized
  Intellectual disability
  Megalencephaly-capillary malformation-polymicrogyria syndrome
  Neurodevelopmental disorder
  Rheumatoid arthritis
  Schizophrenia
  Autism
  Movement disorder
  Stroke
  Autosomal dominant non-syndromic intellectual disability
  Myoclonic-astatic epilepsy
  SYNGAP1-related developmental and epileptic encephalopathy
  Autism spectrum disorder
  Multiple acyl-CoA dehydrogenase deficiency
• UniProt ID: SYGP1_HUMAN
• Pfam ID: PF00168 ; PF12004 ; PF00616
• Sequence:
  MSRSRASIHRGSIPAMSYAPFRDVRGPSMHRTQYVHSPYDRPGWNPRFCIISGNQLLMLD
  EDEIHPLLIRDRRSESSRNKLLRRTVSVPVEGRPHGEHEYHLGRSRRKSVPGGKQYSMEG
  APAAPFRPSQGFLSRRLKSSIKRTKSQPKLDRTSSFRQILPRFRSADHDRARLMQSFKES
  HSHESLLSPSSAAEALELNLDEDSIIKPVHSSILGQEFCFEVTTSSGTKCFACRSAAERD
  KWIENLQRAVKPNKDNSRRVDNVLKLWIIEARELPPKKRYYCELCLDDMLYARTTSKPRS
  ASGDTVFWGEHFEFNNLPAVRALRLHLYRDSDKKRKKDKAGYVGLVTVPVATLAGRHFTE
  QWYPVTLPTGSGGSGGMGSGGGGGSGGGSGGKGKGGCPAVRLKARYQTMSILPMELYKEF
  AEYVTNHYRMLCAVLEPALNVKGKEEVASALVHILQSTGKAKDFLSDMAMSEVDRFMERE
  HLIFRENTLATKAIEEYMRLIGQKYLKDAIGEFIRALYESEENCEVDPIKCTASSLAEHQ
  ANLRMCCELALCKVVNSHCVFPRELKEVFASWRLRCAERGREDIADRLISASLFLRFLCP
  AIMSPSLFGLMQEYPDEQTSRTLTLIAKVIQNLANFSKFTSKEDFLGFMNEFLELEWGSM
  QQFLYEISNLDTLTNSSSFEGYIDLGRELSTLHALLWEVLPQLSKEALLKLGPLPRLLND
  ISTALRNPNIQRQPSRQSERPRPQPVVLRGPSAEMQGYMMRDLNSSIDLQSFMARGLNSS
  MDMARLPSPTKEKPPPPPPGGGKDLFYVSRPPLARSSPAYCTSSSDITEPEQKMLSVNKS
  VSMLDLQGDGPGGRLNSSSVSNLAAVGDLLHSSQASLTAALGLRPAPAGRLSQGSGSSIT
  AAGMRLSQMGVTTDGVPAQQLRIPLSFQNPLFHMAADGPGPPGGHGGGGGHGPPSSHHHH
  HHHHHHRGGEPPGDTFAPFHGYSKSEDLSSGVPKPPAASILHSHSYSDEFGPSGTDFTRR
  QLSLQDNLQHMLSPPQITIGPQRPAPSGPGGGSGGGSGGGGGGQPPPLQRGKSQQLTVSA
  AQKPRPSSGNLLQSPEPSYGPARPRQQSLSKEGSIGGSGGSGGGGGGGLKPSITKQHSQT
  PSTLNPTMPASERTVAWVSNMPHLSADIESAHIEREEYKLKEYSKSMDESRLDRVKEYEE
  EIHSLKERLHMSNRKLEEYERRLLSQEEQTSKILMQYQARLEQSEKRLRQQQAEKDSQIK
  SIIGRLMLVEEELRRDHPAMAEPLPEPKKRLLDAQERQLPPLGPTNPRVTLAPPWNGLAP
  PAPPPPPRLQITENGEFRNTADH
• Function: Major constituent of the PSD essential for postsynaptic signaling. Inhibitory regulator of the Ras-cAMP pathway. Member of the NMDAR signaling complex in excitatory synapses, it may play a role in NMDAR-dependent control of AMPAR potentiation, AMPAR membrane trafficking and synaptic plasticity. Regulates AMPAR-mediated miniature excitatory postsynaptic currents. Exhibits dual GTPase-activating specificity for Ras and Rap. May be involved in certain forms of brain injury, leading to long-term learning and memory deficits.
• KEGG Pathway: Ras sig.ling pathway (hsa04014)
• Reactome Pathway: Regulation of RAS by GAPs (R-HSA-5658442)

Molecular Interaction Atlas (MIA) of This DOT

23 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Blepharospasm	DISJRMG0	Definitive	Biomarker	[1]
Cognitive impairment	DISH2ERD	Definitive	Altered Expression	[2]
Complex neurodevelopmental disorder	DISB9AFI	Definitive	Autosomal dominant	[3]
Intellectual disability, autosomal dominant 5	DISIH9G4	Definitive	Autosomal dominant	[4]
Nervous system disease	DISJ7GGT	Definitive	Genetic Variation	[5]
Brain disease	DIS6ZC3X	Strong	Biomarker	[6]
Capillary malformation-arteriovenous malformation syndrome	DISMN03Q	Strong	Genetic Variation	[7]
Dowling-Degos disease	DISGTTEP	Strong	Genetic Variation	[8]
Epilepsy	DISBB28L	Strong	Genetic Variation	[9]
Epilepsy, idiopathic generalized	DISODZC9	Strong	Genetic Variation	[10]
Intellectual disability	DISMBNXP	Strong	Biomarker	[9]
Megalencephaly-capillary malformation-polymicrogyria syndrome	DISAHLVO	Strong	Genetic Variation	[11]
Neurodevelopmental disorder	DIS372XH	Strong	Genetic Variation	[9]
Rheumatoid arthritis	DISTSB4J	Strong	Genetic Variation	[12]
Schizophrenia	DISSRV2N	Strong	Biomarker	[13]
Autism	DISV4V1Z	moderate	Biomarker	[14]
Movement disorder	DISOJJ2D	moderate	CausalMutation	[15]
Stroke	DISX6UHX	moderate	Biomarker	[16]
Autosomal dominant non-syndromic intellectual disability	DISD6L06	Supportive	Autosomal dominant	[17]
Myoclonic-astatic epilepsy	DISTAVMU	Supportive	Unknown	[18]
SYNGAP1-related developmental and epileptic encephalopathy	DISY3ACD	Supportive	Autosomal dominant	[19]
Autism spectrum disorder	DISXK8NV	Limited	Biomarker	[20]
Multiple acyl-CoA dehydrogenase deficiency	DISEFBN7	Limited	Biomarker	[21]

6 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Ras/Rap GTPase-activating protein SynGAP (SYNGAP1).	[22]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Ras/Rap GTPase-activating protein SynGAP (SYNGAP1).	[23]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Ras/Rap GTPase-activating protein SynGAP (SYNGAP1).	[24]
Marinol	DM70IK5	Approved	Marinol increases the expression of Ras/Rap GTPase-activating protein SynGAP (SYNGAP1).	[26]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Ras/Rap GTPase-activating protein SynGAP (SYNGAP1).	[28]
Glyphosate	DM0AFY7	Investigative	Glyphosate decreases the expression of Ras/Rap GTPase-activating protein SynGAP (SYNGAP1).	[30]

3 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Triclosan	DMZUR4N	Approved	Triclosan increases the methylation of Ras/Rap GTPase-activating protein SynGAP (SYNGAP1).	[25]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Ras/Rap GTPase-activating protein SynGAP (SYNGAP1).	[27]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the methylation of Ras/Rap GTPase-activating protein SynGAP (SYNGAP1).	[29]

References

• [1] Pharmacoresistant epileptic eyelid twitching in a child with a mutation in SYNGAP1.Epileptic Disord. 2017 Sep 1;19(3):339-344. doi: 10.1684/epd.2017.0922.
• [2] Decrease of SYNGAP1 in GABAergic cells impairs inhibitory synapse connectivity, synaptic inhibition and cognitive function.Nat Commun. 2016 Nov 9;7:13340. doi: 10.1038/ncomms13340.
• [3] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [4] De novo SYNGAP1 mutations in nonsyndromic intellectual disability and autism. Biol Psychiatry. 2011 May 1;69(9):898-901. doi: 10.1016/j.biopsych.2010.11.015. Epub 2011 Jan 15.
• [5] Chronic treatment with a MEK inhibitor reverses enhanced excitatory field potentials in Syngap1(+/-) mice.Pharmacol Rep. 2018 Aug;70(4):777-783. doi: 10.1016/j.pharep.2018.02.021. Epub 2018 Jun 23.
• [6] Species-conserved SYNGAP1 phenotypes associated with neurodevelopmental disorders.Mol Cell Neurosci. 2018 Sep;91:140-150. doi: 10.1016/j.mcn.2018.03.008. Epub 2018 Mar 24.
• [7] A novel RASA1 mutation causing capillary malformation-arteriovenous malformation (CM-AVM): the first genetic clinical report in East Asia.Hereditas. 2018 Jul 16;155:24. doi: 10.1186/s41065-018-0062-8. eCollection 2018.
• [8] De novo, heterozygous, loss-of-function mutations in SYNGAP1 cause a syndromic form of intellectual disability.Am J Med Genet A. 2015 Oct;167A(10):2231-7. doi: 10.1002/ajmg.a.37189. Epub 2015 Jun 15.
• [9] SYNGAP1 mutations: Clinical, genetic, and pathophysiological features.Int J Dev Neurosci. 2019 Nov;78:65-76. doi: 10.1016/j.ijdevneu.2019.08.003. Epub 2019 Aug 24.
• [10] 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. 2019 Feb;65:131-137. doi: 10.1016/j.seizure.2018.12.020. Epub 2018 Dec 22.
• [11] Neurocutaneous vascular syndromes.Childs Nerv Syst. 2010 Oct;26(10):1407-15. doi: 10.1007/s00381-010-1201-3. Epub 2010 Jun 27.
• [12] REL, encoding a member of the NF-kappaB family of transcription factors, is a newly defined risk locus for rheumatoid arthritis.Nat Genet. 2009 Jul;41(7):820-3. doi: 10.1038/ng.395. Epub 2009 Jun 7.
• [13] Comprehensive functional annotation of susceptibility SNPs prioritized 10 genes for schizophrenia.Transl Psychiatry. 2019 Jan 31;9(1):56. doi: 10.1038/s41398-019-0398-5.
• [14] First International Conference on RASopathies and Neurofibromatoses in Asia: Identification and advances of new therapeutics.Am J Med Genet A. 2019 Jun;179(6):1091-1097. doi: 10.1002/ajmg.a.61125. Epub 2019 Mar 25.
• [15] Analysis of 31-year-old patient with SYNGAP1 gene defect points to importance of variants in broader splice regions and reveals developmental trajectory of SYNGAP1-associated phenotype: case report.BMC Med Genet. 2017 Jun 2;18(1):62. doi: 10.1186/s12881-017-0425-4.
• [16] Tau exacerbates excitotoxic brain damage in an animal model of stroke.Nat Commun. 2017 Sep 7;8(1):473. doi: 10.1038/s41467-017-00618-0.
• [17] Mutations in SYNGAP1 cause intellectual disability, autism, and a specific form of epilepsy by inducing haploinsufficiency. Hum Mutat. 2013 Feb;34(2):385-94. doi: 10.1002/humu.22248. Epub 2012 Dec 12.
• [18] Phenotypic and genetic spectrum of epilepsy with myoclonic atonic seizures. Epilepsia. 2020 May;61(5):995-1007. doi: 10.1111/epi.16508. Epub 2020 May 29.
• [19] SYNGAP1 encephalopathy: A distinctive generalized developmental and epileptic encephalopathy. Neurology. 2019 Jan 8;92(2):e96-e107. doi: 10.1212/WNL.0000000000006729. Epub 2018 Dec 12.
• [20] Autism-associated missense genetic variants impact locomotion and neurodevelopment in Caenorhabditis elegans.Hum Mol Genet. 2019 Jul 1;28(13):2271-2281. doi: 10.1093/hmg/ddz051.
• [21] A balanced translocation disrupts SYNGAP1 in a patient with intellectual disability, speech impairment, and epilepsy with myoclonic absences (EMA).Epilepsia. 2011 Dec;52(12):e190-3. doi: 10.1111/j.1528-1167.2011.03304.x. Epub 2011 Nov 2.
• [22] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [23] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [24] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [25] Pregnancy exposure to synthetic phenols and placental DNA methylation - An epigenome-wide association study in male infants from the EDEN cohort. Environ Pollut. 2021 Dec 1;290:118024. doi: 10.1016/j.envpol.2021.118024. Epub 2021 Aug 21.
• [26] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
• [27] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [28] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [29] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [30] Glyphosate-based herbicides at low doses affect canonical pathways in estrogen positive and negative breast cancer cell lines. PLoS One. 2019 Jul 11;14(7):e0219610. doi: 10.1371/journal.pone.0219610. eCollection 2019.