Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTUSYE4Z)

• DOT Name: Sodium channel protein type 2 subunit alpha (SCN2A)
• Synonyms: HBSC II; Sodium channel protein brain II subunit alpha; Sodium channel protein type II subunit alpha; Voltage-gated sodium channel subunit alpha Nav1.2
• Gene Name: SCN2A
• Related Disease:
  Complex neurodevelopmental disorder
  Developmental and epileptic encephalopathy, 11
  Seizures, benign familial infantile, 3
  Benign familial infantile epilepsy
  Infantile spasm
  Malignant migrating partial seizures of infancy
  Obsolete benign familial neonatal-infantile seizures
  Obsolete Dravet syndrome
  West syndrome
• UniProt ID: SCN2A_HUMAN
• PDB ID: 2KAV; 4JPZ; 4RLY; 6BUT; 6J8E
• Pfam ID: PF00520 ; PF06512 ; PF11933
• Sequence:
  MAQSVLVPPGPDSFRFFTRESLAAIEQRIAEEKAKRPKQERKDEDDENGPKPNSDLEAGK
  SLPFIYGDIPPEMVSVPLEDLDPYYINKKTFIVLNKGKAISRFSATPALYILTPFNPIRK
  LAIKILVHSLFNMLIMCTILTNCVFMTMSNPPDWTKNVEYTFTGIYTFESLIKILARGFC
  LEDFTFLRDPWNWLDFTVITFAYVTEFVDLGNVSALRTFRVLRALKTISVIPGLKTIVGA
  LIQSVKKLSDVMILTVFCLSVFALIGLQLFMGNLRNKCLQWPPDNSSFEINITSFFNNSL
  DGNGTTFNRTVSIFNWDEYIEDKSHFYFLEGQNDALLCGNSSDAGQCPEGYICVKAGRNP
  NYGYTSFDTFSWAFLSLFRLMTQDFWENLYQLTLRAAGKTYMIFFVLVIFLGSFYLINLI
  LAVVAMAYEEQNQATLEEAEQKEAEFQQMLEQLKKQQEEAQAAAAAASAESRDFSGAGGI
  GVFSESSSVASKLSSKSEKELKNRRKKKKQKEQSGEEEKNDRVRKSESEDSIRRKGFRFS
  LEGSRLTYEKRFSSPHQSLLSIRGSLFSPRRNSRASLFSFRGRAKDIGSENDFADDEHST
  FEDNDSRRDSLFVPHRHGERRHSNVSQASRASRVLPILPMNGKMHSAVDCNGVVSLVGGP
  STLTSAGQLLPEGTTTETEIRKRRSSSYHVSMDLLEDPTSRQRAMSIASILTNTMEELEE
  SRQKCPPCWYKFANMCLIWDCCKPWLKVKHLVNLVVMDPFVDLAITICIVLNTLFMAMEH
  YPMTEQFSSVLSVGNLVFTGIFTAEMFLKIIAMDPYYYFQEGWNIFDGFIVSLSLMELGL
  ANVEGLSVLRSFRLLRVFKLAKSWPTLNMLIKIIGNSVGALGNLTLVLAIIVFIFAVVGM
  QLFGKSYKECVCKISNDCELPRWHMHDFFHSFLIVFRVLCGEWIETMWDCMEVAGQTMCL
  TVFMMVMVIGNLVVLNLFLALLLSSFSSDNLAATDDDNEMNNLQIAVGRMQKGIDFVKRK
  IREFIQKAFVRKQKALDEIKPLEDLNNKKDSCISNHTTIEIGKDLNYLKDGNGTTSGIGS
  SVEKYVVDESDYMSFINNPSLTVTVPIAVGESDFENLNTEEFSSESDMEESKEKLNATSS
  SEGSTVDIGAPAEGEQPEVEPEESLEPEACFTEDCVRKFKCCQISIEEGKGKLWWNLRKT
  CYKIVEHNWFETFIVFMILLSSGALAFEDIYIEQRKTIKTMLEYADKVFTYIFILEMLLK
  WVAYGFQVYFTNAWCWLDFLIVDVSLVSLTANALGYSELGAIKSLRTLRALRPLRALSRF
  EGMRVVVNALLGAIPSIMNVLLVCLIFWLIFSIMGVNLFAGKFYHCINYTTGEMFDVSVV
  NNYSECKALIESNQTARWKNVKVNFDNVGLGYLSLLQVATFKGWMDIMYAAVDSRNVELQ
  PKYEDNLYMYLYFVIFIIFGSFFTLNLFIGVIIDNFNQQKKKFGGQDIFMTEEQKKYYNA
  MKKLGSKKPQKPIPRPANKFQGMVFDFVTKQVFDISIMILICLNMVTMMVETDDQSQEMT
  NILYWINLVFIVLFTGECVLKLISLRYYYFTIGWNIFDFVVVILSIVGMFLAELIEKYFV
  SPTLFRVIRLARIGRILRLIKGAKGIRTLLFALMMSLPALFNIGLLLFLVMFIYAIFGMS
  NFAYVKREVGIDDMFNFETFGNSMICLFQITTSAGWDGLLAPILNSGPPDCDPDKDHPGS
  SVKGDCGNPSVGIFFFVSYIIISFLVVVNMYIAVILENFSVATEESAEPLSEDDFEMFYE
  VWEKFDPDATQFIEFAKLSDFADALDPPLLIAKPNKVQLIAMDLPMVSGDRIHCLDILFA
  FTKRVLGESGEMDALRIQMEERFMASNPSKVSYEPITTTLKRKQEEVSAIIIQRAYRRYL
  LKQKVKKVSSIYKKDKGKECDGTPIKEDTLIDKLNENSTPEKTDMTPSTTSPPSYDSVTK
  PEKEKFEKDKSEKEDKGKDIRESKK
• 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. Implicated in the regulation of hippocampal replay occurring within sharp wave ripples (SPW-R) important for memory.
• KEGG Pathway: Taste transduction (hsa04742)
• Reactome Pathway:
  Phase 0 - rapid depolarisation (R-HSA-5576892)
  Sensory perception of sweet, bitter, and umami (glutamate) taste (R-HSA-9717207)
  Interaction between L1 and Ankyrins (R-HSA-445095)

Molecular Interaction Atlas (MIA) of This DOT

9 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Complex neurodevelopmental disorder	DISB9AFI	Definitive	Autosomal dominant	[1]
Developmental and epileptic encephalopathy, 11	DIS5NN8A	Definitive	Autosomal dominant	[2]
Seizures, benign familial infantile, 3	DISF5P7A	Strong	Autosomal dominant	[2]
Benign familial infantile epilepsy	DISFYXOW	Supportive	Autosomal dominant	[3]
Infantile spasm	DISZSKDG	Supportive	Autosomal dominant	[4]
Malignant migrating partial seizures of infancy	DISF2TRU	Supportive	Autosomal dominant	[5]
Obsolete benign familial neonatal-infantile seizures	DISQVTP9	Supportive	Autosomal dominant	[6]
Obsolete Dravet syndrome	DISM4LMK	Supportive	Autosomal dominant	[7]
West syndrome	DISLIAU9	Supportive	Autosomal dominant	[8]

10 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 2 subunit alpha (SCN2A).	[9]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Sodium channel protein type 2 subunit alpha (SCN2A).	[11]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Sodium channel protein type 2 subunit alpha (SCN2A).	[12]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Sodium channel protein type 2 subunit alpha (SCN2A).	[13]
Marinol	DM70IK5	Approved	Marinol decreases the activity of Sodium channel protein type 2 subunit alpha (SCN2A).	[14]
Cannabidiol	DM0659E	Approved	Cannabidiol decreases the activity of Sodium channel protein type 2 subunit alpha (SCN2A).	[14]
Phenytoin	DMNOKBV	Approved	Phenytoin decreases the activity of Sodium channel protein type 2 subunit alpha (SCN2A).	[15]
Lamotrigine	DM8SXYG	Approved	Lamotrigine decreases the activity of Sodium channel protein type 2 subunit alpha (SCN2A).	[15]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Sodium channel protein type 2 subunit alpha (SCN2A).	[17]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN increases the expression of Sodium channel protein type 2 subunit alpha (SCN2A).	[18]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the methylation of Sodium channel protein type 2 subunit alpha (SCN2A).	[10]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Sodium channel protein type 2 subunit alpha (SCN2A).	[16]

References

• [1] 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.
• [2] 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.
• [3] Genetic testing in benign familial epilepsies of the first year of life: clinical and diagnostic significance. Epilepsia. 2013 Mar;54(3):425-36. doi: 10.1111/epi.12089. Epub 2013 Jan 29.
• [4] Whole genome sequencing identifies SCN2A mutation in monozygotic twins with Ohtahara syndrome and unique neuropathologic findings. Epilepsia. 2013 May;54(5):e81-5. doi: 10.1111/epi.12137. Epub 2013 Mar 28.
• [5] The Genetic Landscape of Epilepsy of Infancy with Migrating Focal Seizures. Ann Neurol. 2019 Dec;86(6):821-831. doi: 10.1002/ana.25619.
• [6] Sodium-channel defects in benign familial neonatal-infantile seizures. Lancet. 2002 Sep 14;360(9336):851-2. doi: 10.1016/S0140-6736(02)09968-3.
• [7] Missense mutation of the sodium channel gene SCN2A causes Dravet syndrome. Brain Dev. 2009 Nov;31(10):758-62. doi: 10.1016/j.braindev.2009.08.009. Epub 2009 Sep 23.
• [8] Clinical spectrum of SCN2A mutations expanding to Ohtahara syndrome. Neurology. 2013 Sep 10;81(11):992-8. doi: 10.1212/WNL.0b013e3182a43e57. Epub 2013 Aug 9.
• [9] The neuroprotective action of the mood stabilizing drugs lithium chloride and sodium valproate is mediated through the up-regulation of the homeodomain protein Six1. Toxicol Appl Pharmacol. 2009 Feb 15;235(1):124-34.
• [10] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [11] Selective Recognition of H3.1K36 Dimethylation/H4K16 Acetylation Facilitates the Regulation of All-trans-retinoic Acid (ATRA)-responsive Genes by Putative Chromatin Reader ZMYND8. J Biol Chem. 2016 Feb 5;291(6):2664-81. doi: 10.1074/jbc.M115.679985. Epub 2015 Dec 11.
• [12] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [13] Identification of transcriptome signatures and biomarkers specific for potential developmental toxicants inhibiting human neural crest cell migration. Arch Toxicol. 2016 Jan;90(1):159-80.
• [14] 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.
• [15] Electrophysiological and pharmacological properties of the human brain type IIA Na+ channel expressed in a stable mammalian cell line. Pflugers Arch. 2001 Jan;441(4):425-33. doi: 10.1007/s004240000448.
• [16] 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.
• [17] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [18] The genome-wide expression profile of Scrophularia ningpoensis-treated thapsigargin-stimulated U-87MG cells. Neurotoxicology. 2009 May;30(3):368-76.