Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT0JGIZN)

• DOT Name: Sodium channel protein type 8 subunit alpha (SCN8A)
• Synonyms: Sodium channel protein type VIII subunit alpha; Voltage-gated sodium channel subunit alpha Nav1.6
• Gene Name: SCN8A
• Related Disease:
  Cognitive impairment with or without cerebellar ataxia
  Complex neurodevelopmental disorder
  Developmental and epileptic encephalopathy, 13
  Seizures, benign familial infantile, 5
  Benign familial infantile epilepsy
  Infantile convulsions and choreoathetosis
  Undetermined early-onset epileptic encephalopathy
  Myoclonus, familial, 2
• UniProt ID: SCN8A_HUMAN
• PDB ID: 8FHD; 8GZ1; 8GZ2
• Pfam ID: PF00520 ; PF00612 ; PF06512 ; PF11933
• Sequence:
  MAARLLAPPGPDSFKPFTPESLANIERRIAESKLKKPPKADGSHREDDEDSKPKPNSDLE
  AGKSLPFIYGDIPQGLVAVPLEDFDPYYLTQKTFVVLNRGKTLFRFSATPALYILSPFNL
  IRRIAIKILIHSVFSMIIMCTILTNCVFMTFSNPPDWSKNVEYTFTGIYTFESLVKIIAR
  GFCIDGFTFLRDPWNWLDFSVIMMAYITEFVNLGNVSALRTFRVLRALKTISVIPGLKTI
  VGALIQSVKKLSDVMILTVFCLSVFALIGLQLFMGNLRNKCVVWPINFNESYLENGTKGF
  DWEEYINNKTNFYTVPGMLEPLLCGNSSDAGQCPEGYQCMKAGRNPNYGYTSFDTFSWAF
  LALFRLMTQDYWENLYQLTLRAAGKTYMIFFVLVIFVGSFYLVNLILAVVAMAYEEQNQA
  TLEEAEQKEAEFKAMLEQLKKQQEEAQAAAMATSAGTVSEDAIEEEGEEGGGSPRSSSEI
  SKLSSKSAKERRNRRKKRKQKELSEGEEKGDPEKVFKSESEDGMRRKAFRLPDNRIGRKF
  SIMNQSLLSIPGSPFLSRHNSKSSIFSFRGPGRFRDPGSENEFADDEHSTVEESEGRRDS
  LFIPIRARERRSSYSGYSGYSQGSRSSRIFPSLRRSVKRNSTVDCNGVVSLIGGPGSHIG
  GRLLPEATTEVEIKKKGPGSLLVSMDQLASYGRKDRINSIMSVVTNTLVEELEESQRKCP
  PCWYKFANTFLIWECHPYWIKLKEIVNLIVMDPFVDLAITICIVLNTLFMAMEHHPMTPQ
  FEHVLAVGNLVFTGIFTAEMFLKLIAMDPYYYFQEGWNIFDGFIVSLSLMELSLADVEGL
  SVLRSFRLLRVFKLAKSWPTLNMLIKIIGNSVGALGNLTLVLAIIVFIFAVVGMQLFGKS
  YKECVCKINQDCELPRWHMHDFFHSFLIVFRVLCGEWIETMWDCMEVAGQAMCLIVFMMV
  MVIGNLVVLNLFLALLLSSFSADNLAATDDDGEMNNLQISVIRIKKGVAWTKLKVHAFMQ
  AHFKQREADEVKPLDELYEKKANCIANHTGADIHRNGDFQKNGNGTTSGIGSSVEKYIID
  EDHMSFINNPNLTVRVPIAVGESDFENLNTEDVSSESDPEGSKDKLDDTSSSEGSTIDIK
  PEVEEVPVEQPEEYLDPDACFTEGCVQRFKCCQVNIEEGLGKSWWILRKTCFLIVEHNWF
  ETFIIFMILLSSGALAFEDIYIEQRKTIRTILEYADKVFTYIFILEMLLKWTAYGFVKFF
  TNAWCWLDFLIVAVSLVSLIANALGYSELGAIKSLRTLRALRPLRALSRFEGMRVVVNAL
  VGAIPSIMNVLLVCLIFWLIFSIMGVNLFAGKYHYCFNETSEIRFEIEDVNNKTECEKLM
  EGNNTEIRWKNVKINFDNVGAGYLALLQVATFKGWMDIMYAAVDSRKPDEQPKYEDNIYM
  YIYFVIFIIFGSFFTLNLFIGVIIDNFNQQKKKFGGQDIFMTEEQKKYYNAMKKLGSKKP
  QKPIPRPLNKIQGIVFDFVTQQAFDIVIMMLICLNMVTMMVETDTQSKQMENILYWINLV
  FVIFFTCECVLKMFALRHYYFTIGWNIFDFVVVILSIVGMFLADIIEKYFVSPTLFRVIR
  LARIGRILRLIKGAKGIRTLLFALMMSLPALFNIGLLLFLVMFIFSIFGMSNFAYVKHEA
  GIDDMFNFETFGNSMICLFQITTSAGWDGLLLPILNRPPDCSLDKEHPGSGFKGDCGNPS
  VGIFFFVSYIIISFLIVVNMYIAIILENFSVATEESADPLSEDDFETFYEIWEKFDPDAT
  QFIEYCKLADFADALEHPLRVPKPNTIELIAMDLPMVSGDRIHCLDILFAFTKRVLGDSG
  ELDILRQQMEERFVASNPSKVSYEPITTTLRRKQEEVSAVVLQRAYRGHLARRGFICKKT
  TSNKLENGGTHREKKESTPSTASLPSYDSVTKPEKEKQQRAEEGRRERAKRQKEVRESKC
• 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; [Isoform 5]: In macrophages and melanoma cells, may participate in the control of podosome and invadopodia formation.
• Tissue Specificity: Expressed in the hippocampus with increased expression in epileptic tissue compared to normal adjacent tissue (at protein level) . Isoform 5: Expressed in non-neuronal tissues, such as monocytes/macrophages.
• Reactome Pathway:
  Phase 0 - rapid depolarisation (R-HSA-5576892)
  Interaction between L1 and Ankyrins (R-HSA-445095)

Molecular Interaction Atlas (MIA) of This DOT

8 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Cognitive impairment with or without cerebellar ataxia	DIS9M0JX	Definitive	Autosomal dominant	[1]
Complex neurodevelopmental disorder	DISB9AFI	Definitive	Autosomal dominant	[2]
Developmental and epileptic encephalopathy, 13	DISXSVTK	Definitive	Autosomal dominant	[3]
Seizures, benign familial infantile, 5	DISYA1KR	Strong	Autosomal dominant	[4]
Benign familial infantile epilepsy	DISFYXOW	Supportive	Autosomal dominant	[5]
Infantile convulsions and choreoathetosis	DIS0H0JE	Supportive	Autosomal dominant	[5]
Undetermined early-onset epileptic encephalopathy	DISISEI2	Supportive	Autosomal dominant	[6]
Myoclonus, familial, 2	DIS6EXL2	Limited	Autosomal dominant	[3]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Temozolomide	DMKECZD	Approved	Sodium channel protein type 8 subunit alpha (SCN8A) affects the response to substance of Temozolomide.	[14]
DTI-015	DMXZRW0	Approved	Sodium channel protein type 8 subunit alpha (SCN8A) affects the response to substance of DTI-015.	[14]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Sodium channel protein type 8 subunit alpha (SCN8A).	[7]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Sodium channel protein type 8 subunit alpha (SCN8A).	[12]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Sodium channel protein type 8 subunit alpha (SCN8A).	[8]
Cannabidiol	DM0659E	Approved	Cannabidiol decreases the activity of Sodium channel protein type 8 subunit alpha (SCN8A).	[9]
Melphalan	DMOLNHF	Approved	Melphalan decreases the expression of Sodium channel protein type 8 subunit alpha (SCN8A).	[10]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of Sodium channel protein type 8 subunit alpha (SCN8A).	[11]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Sodium channel protein type 8 subunit alpha (SCN8A).	[13]

References

• [1] Heterozygosity for a protein truncation mutation of sodium channel SCN8A in a patient with cerebellar atrophy, ataxia, and mental retardation. J Med Genet. 2006 Jun;43(6):527-30. doi: 10.1136/jmg.2005.035667. Epub 2005 Oct 19.
• [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] Autosomal dominant SCN8A mutation with an unusually mild phenotype. Eur J Paediatr Neurol. 2016 Sep;20(5):761-5. doi: 10.1016/j.ejpn.2016.04.015. Epub 2016 Apr 30.
• [5] Benign infantile seizures and paroxysmal dyskinesia caused by an SCN8A mutation. Ann Neurol. 2016 Mar;79(3):428-36. doi: 10.1002/ana.24580. Epub 2016 Feb 13.
• [6] De novo pathogenic SCN8A mutation identified by whole-genome sequencing of a family quartet affected by infantile epileptic encephalopathy and SUDEP. Am J Hum Genet. 2012 Mar 9;90(3):502-10. doi: 10.1016/j.ajhg.2012.01.006. Epub 2012 Feb 23.
• [7] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [8] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [9] 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.
• [10] Bone marrow osteoblast damage by chemotherapeutic agents. PLoS One. 2012;7(2):e30758. doi: 10.1371/journal.pone.0030758. Epub 2012 Feb 17.
• [11] Changes in gene expressions elicited by physiological concentrations of genistein on human endometrial cancer cells. Mol Carcinog. 2006 Oct;45(10):752-63.
• [12] 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.
• [13] 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.
• [14] Tumor necrosis factor-alpha-induced protein 3 as a putative regulator of nuclear factor-kappaB-mediated resistance to O6-alkylating agents in human glioblastomas. J Clin Oncol. 2006 Jan 10;24(2):274-87. doi: 10.1200/JCO.2005.02.9405. Epub 2005 Dec 19.