Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTJ9ZTYI)

• DOT Name: Sodium channel protein type 1 subunit alpha (SCN1A)
• Synonyms: Sodium channel protein brain I subunit alpha; Sodium channel protein type I subunit alpha; Voltage-gated sodium channel subunit alpha Nav1.1
• Gene Name: SCN1A
• Related Disease:
  Developmental and epileptic encephalopathy, 6
  Dravet syndrome
  Generalized epilepsy with febrile seizures plus
  Generalized epilepsy with febrile seizures plus, type 2
  Infantile spasm
  Migraine, familial hemiplegic, 3
  Arthrogryposis
  Familial hemiplegic migraine
  Familial or sporadic hemiplegic migraine
  LennoxGastaut syndrome
  Malignant migrating partial seizures of infancy
  Myoclonic-astatic epilepsy
  Obsolete Dravet syndrome
• UniProt ID: SCN1A_HUMAN
• PDB ID: 7DTD
• Pfam ID: PF00520 ; PF06512 ; PF11933
• Sequence:
  MEQTVLVPPGPDSFNFFTRESLAAIERRIAEEKAKNPKPDKKDDDENGPKPNSDLEAGKN
  LPFIYGDIPPEMVSEPLEDLDPYYINKKTFIVLNKGKAIFRFSATSALYILTPFNPLRKI
  AIKILVHSLFSMLIMCTILTNCVFMTMSNPPDWTKNVEYTFTGIYTFESLIKIIARGFCL
  EDFTFLRDPWNWLDFTVITFAYVTEFVDLGNVSALRTFRVLRALKTISVIPGLKTIVGAL
  IQSVKKLSDVMILTVFCLSVFALIGLQLFMGNLRNKCIQWPPTNASLEEHSIEKNITVNY
  NGTLINETVFEFDWKSYIQDSRYHYFLEGFLDALLCGNSSDAGQCPEGYMCVKAGRNPNY
  GYTSFDTFSWAFLSLFRLMTQDFWENLYQLTLRAAGKTYMIFFVLVIFLGSFYLINLILA
  VVAMAYEEQNQATLEEAEQKEAEFQQMIEQLKKQQEAAQQAATATASEHSREPSAAGRLS
  DSSSEASKLSSKSAKERRNRRKKRKQKEQSGGEEKDEDEFQKSESEDSIRRKGFRFSIEG
  NRLTYEKRYSSPHQSLLSIRGSLFSPRRNSRTSLFSFRGRAKDVGSENDFADDEHSTFED
  NESRRDSLFVPRRHGERRNSNLSQTSRSSRMLAVFPANGKMHSTVDCNGVVSLVGGPSVP
  TSPVGQLLPEVIIDKPATDDNGTTTETEMRKRRSSSFHVSMDFLEDPSQRQRAMSIASIL
  TNTVEELEESRQKCPPCWYKFSNIFLIWDCSPYWLKVKHVVNLVVMDPFVDLAITICIVL
  NTLFMAMEHYPMTDHFNNVLTVGNLVFTGIFTAEMFLKIIAMDPYYYFQEGWNIFDGFIV
  TLSLVELGLANVEGLSVLRSFRLLRVFKLAKSWPTLNMLIKIIGNSVGALGNLTLVLAII
  VFIFAVVGMQLFGKSYKDCVCKIASDCQLPRWHMNDFFHSFLIVFRVLCGEWIETMWDCM
  EVAGQAMCLTVFMMVMVIGNLVVLNLFLALLLSSFSADNLAATDDDNEMNNLQIAVDRMH
  KGVAYVKRKIYEFIQQSFIRKQKILDEIKPLDDLNNKKDSCMSNHTAEIGKDLDYLKDVN
  GTTSGIGTGSSVEKYIIDESDYMSFINNPSLTVTVPIAVGESDFENLNTEDFSSESDLEE
  SKEKLNESSSSSEGSTVDIGAPVEEQPVVEPEETLEPEACFTEGCVQRFKCCQINVEEGR
  GKQWWNLRRTCFRIVEHNWFETFIVFMILLSSGALAFEDIYIDQRKTIKTMLEYADKVFT
  YIFILEMLLKWVAYGYQTYFTNAWCWLDFLIVDVSLVSLTANALGYSELGAIKSLRTLRA
  LRPLRALSRFEGMRVVVNALLGAIPSIMNVLLVCLIFWLIFSIMGVNLFAGKFYHCINTT
  TGDRFDIEDVNNHTDCLKLIERNETARWKNVKVNFDNVGFGYLSLLQVATFKGWMDIMYA
  AVDSRNVELQPKYEESLYMYLYFVIFIIFGSFFTLNLFIGVIIDNFNQQKKKFGGQDIFM
  TEEQKKYYNAMKKLGSKKPQKPIPRPGNKFQGMVFDFVTRQVFDISIMILICLNMVTMMV
  ETDDQSEYVTTILSRINLVFIVLFTGECVLKLISLRHYYFTIGWNIFDFVVVILSIVGMF
  LAELIEKYFVSPTLFRVIRLARIGRILRLIKGAKGIRTLLFALMMSLPALFNIGLLLFLV
  MFIYAIFGMSNFAYVKREVGIDDMFNFETFGNSMICLFQITTSAGWDGLLAPILNSKPPD
  CDPNKVNPGSSVKGDCGNPSVGIFFFVSYIIISFLVVVNMYIAVILENFSVATEESAEPL
  SEDDFEMFYEVWEKFDPDATQFMEFEKLSQFAAALEPPLNLPQPNKLQLIAMDLPMVSGD
  RIHCLDILFAFTKRVLGESGEMDALRIQMEERFMASNPSKVSYQPITTTLKRKQEEVSAV
  IIQRAYRRHLLKRTVKQASFTYNKNKIKGGANLLIKEDMIIDRINENSITEKTDLTMSTA
  ACPPSYDRVTKPIVEKHEQEGKDEKAKGK
• Function: Mediates the voltage-dependent sodium ion permeability of excitable membranes. Assuming opened or closed conformations in response to the voltage difference across the membrane, the protein forms a sodium-selective channel through which Na(+) ions may pass in accordance with their electrochemical gradient. Plays a key role in brain, probably by regulating the moment when neurotransmitters are released in neurons. Involved in sensory perception of mechanical pain: activation in somatosensory neurons induces pain without neurogenic inflammation and produces hypersensitivity to mechanical, but not thermal stimuli.
• KEGG Pathway: Dopaminergic sy.pse (hsa04728)
• Reactome Pathway:
  Phase 0 - rapid depolarisation (R-HSA-5576892)
  Interaction between L1 and Ankyrins (R-HSA-445095)

Molecular Interaction Atlas (MIA) of This DOT

13 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Developmental and epileptic encephalopathy, 6	DISHGG0A	Definitive	Autosomal dominant	[1]
Dravet syndrome	DISJF7LY	Definitive	Autosomal dominant	[2]
Generalized epilepsy with febrile seizures plus	DISJE0UU	Definitive	Autosomal dominant	[2]
Generalized epilepsy with febrile seizures plus, type 2	DIS58QJS	Definitive	Autosomal dominant	[3]
Infantile spasm	DISZSKDG	Strong	Autosomal dominant	[2]
Migraine, familial hemiplegic, 3	DISMXUGF	Strong	Autosomal dominant	[3]
Arthrogryposis	DISC81CM	Moderate	Autosomal dominant	[4]
Familial hemiplegic migraine	DISYVMKL	Moderate	Autosomal dominant	[2]
Familial or sporadic hemiplegic migraine	DISOSL2O	Supportive	Autosomal dominant	[5]
LennoxGastaut syndrome	DISOTGO5	Supportive	Autosomal dominant	[6]
Malignant migrating partial seizures of infancy	DISF2TRU	Supportive	Autosomal dominant	[7]
Myoclonic-astatic epilepsy	DISTAVMU	Supportive	Unknown	[8]
Obsolete Dravet syndrome	DISM4LMK	Supportive	Autosomal dominant	[9]

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Carbamazepine	DMZOLBI	Approved	Sodium channel protein type 1 subunit alpha (SCN1A) decreases the response to substance of Carbamazepine.	[25]
Phenytoin	DMNOKBV	Approved	Sodium channel protein type 1 subunit alpha (SCN1A) affects the response to substance of Phenytoin.	[26]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Sodium channel protein type 1 subunit alpha (SCN1A).	[10]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Sodium channel protein type 1 subunit alpha (SCN1A).	[11]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Sodium channel protein type 1 subunit alpha (SCN1A).	[12]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Sodium channel protein type 1 subunit alpha (SCN1A).	[13]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Sodium channel protein type 1 subunit alpha (SCN1A).	[14]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Sodium channel protein type 1 subunit alpha (SCN1A).	[16]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Sodium channel protein type 1 subunit alpha (SCN1A).	[17]
Cannabidiol	DM0659E	Approved	Cannabidiol decreases the activity of Sodium channel protein type 1 subunit alpha (SCN1A).	[19]
Azathioprine	DMMZSXQ	Approved	Azathioprine decreases the expression of Sodium channel protein type 1 subunit alpha (SCN1A).	[20]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Sodium channel protein type 1 subunit alpha (SCN1A).	[21]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Sodium channel protein type 1 subunit alpha (SCN1A).	[17]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Sodium channel protein type 1 subunit alpha (SCN1A).	[14]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of Sodium channel protein type 1 subunit alpha (SCN1A).	[22]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Sodium channel protein type 1 subunit alpha (SCN1A).	[23]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of Sodium channel protein type 1 subunit alpha (SCN1A).	[24]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Sodium channel protein type 1 subunit alpha (SCN1A).	[15]
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the methylation of Sodium channel protein type 1 subunit alpha (SCN1A).	[18]

References

• [1] The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources. Genet Med. 2022 Aug;24(8):1732-1742. doi: 10.1016/j.gim.2022.04.017. Epub 2022 May 4.
• [2] 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.
• [3] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [4] De novo mutations of SCN1A are responsible for arthrogryposis broadening the SCN1A-related phenotypes. J Med Genet. 2021 Nov;58(11):737-742. doi: 10.1136/jmedgenet-2020-107166. Epub 2020 Sep 14.
• [5] Familial Hemiplegic Migraine. 2001 Jul 17 [updated 2021 Apr 29]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews(?) [Internet]. Seattle (WA): University of Washington, Seattle; 1993C2024.
• [6] The spectrum of SCN1A-related infantile epileptic encephalopathies. Brain. 2007 Mar;130(Pt 3):843-52. doi: 10.1093/brain/awm002.
• [7] Novel SCN1A mutation in a proband with malignant migrating partial seizures of infancy. Arch Neurol. 2011 May;68(5):665-71. doi: 10.1001/archneurol.2011.98.
• [8] One novel Dravet syndrome causing mutation and one recurrent MAE causing mutation in SCN1A gene. Neurosci Lett. 2011 Apr 25;494(2):180-3. doi: 10.1016/j.neulet.2011.03.008. Epub 2011 Mar 15.
• [9] SCN1A Seizure Disorders. 2007 Nov 29 [updated 2022 Feb 17]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews(?) [Internet]. Seattle (WA): University of Washington, Seattle; 1993C2024.
• [10] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [11] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [12] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [13] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [14] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [15] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [16] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [17] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [18] 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.
• [19] Inhibitory effects of cannabidiol on voltage-dependent sodium currents. J Biol Chem. 2018 Oct 26;293(43):16546-16558. doi: 10.1074/jbc.RA118.004929. Epub 2018 Sep 14.
• [20] A transcriptomics-based in vitro assay for predicting chemical genotoxicity in vivo. Carcinogenesis. 2012 Jul;33(7):1421-9.
• [21] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [22] Comprehensive analysis of transcriptomic changes induced by low and high doses of bisphenol A in HepG2 spheroids in vitro and rat liver in vivo. Environ Res. 2019 Jun;173:124-134. doi: 10.1016/j.envres.2019.03.035. Epub 2019 Mar 18.
• [23] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [24] Transcriptome and DNA methylation changes modulated by sulforaphane induce cell cycle arrest, apoptosis, DNA damage, and suppression of proliferation in human liver cancer cells. Food Chem Toxicol. 2020 Feb;136:111047. doi: 10.1016/j.fct.2019.111047. Epub 2019 Dec 12.
• [25] Association between SCN1A polymorphism and carbamazepine-resistant epilepsy. Br J Clin Pharmacol. 2008 Aug;66(2):304-7. doi: 10.1111/j.1365-2125.2008.03203.x. Epub 2008 Apr 11.
• [26] A common polymorphism in the SCN1A gene associates with phenytoin serum levels at maintenance dose. Pharmacogenet Genomics. 2006 Oct;16(10):721-6. doi: 10.1097/01.fpc.0000230114.41828.73.