Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTNTQT9O)

• DOT Name: Sodium channel regulatory subunit beta-3 (SCN3B)
• Gene Name: SCN3B
• Related Disease:
  Arrhythmia
  Epilepsy
  Paroxysmal familial ventricular fibrillation
  Familial atrial fibrillation
  Brugada syndrome 1
  Conduction system disorder
  Sinoatrial node disorder
  Atrial fibrillation
  Brugada syndrome 7
• UniProt ID: SCN3B_HUMAN
• PDB ID: 4L1D; 7TJ8; 7TJ9
• Pfam ID: PF07686
• Sequence:
  MPAFNRLFPLASLVLIYWVSVCFPVCVEVPSETEAVQGNPMKLRCISCMKREEVEATTVV
  EWFYRPEGGKDFLIYEYRNGHQEVESPFQGRLQWNGSKDLQDVSITVLNVTLNDSGLYTC
  NVSREFEFEAHRPFVKTTRLIPLRVTEEAGEDFTSVVSEIMMYILLVFLTLWLLIEMIYC
  YRKVSKAEEAAQENASDYLAIPSENKENSAVPVEE
• Function: Voltage-gated sodium channels regulatory subunit that modulates channel gating kinetics. Causes unique persistent sodium currents. Inactivates the sodium channel opening more slowly than the subunit beta-1. Its association with NFASC may target the sodium channels to the nodes of Ranvier of developing axons and retain these channels at the nodes in mature myelinated axons.
• Tissue Specificity: Expressed in the atrium.
• Reactome Pathway:
  Phase 0 - rapid depolarisation (R-HSA-5576892)
  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
Arrhythmia	DISFF2NI	Strong	CausalMutation	[1]
Epilepsy	DISBB28L	Strong	Biomarker	[2]
Paroxysmal familial ventricular fibrillation	DISRM7IX	Strong	Genetic Variation	[3]
Familial atrial fibrillation	DISL4AGF	Supportive	Autosomal dominant	[4]
Brugada syndrome 1	DISKBA7V	Disputed	Autosomal dominant	[5]
Conduction system disorder	DISED5HG	Disputed	Biomarker	[6]
Sinoatrial node disorder	DISYJI6J	Disputed	Biomarker	[6]
Atrial fibrillation	DIS15W6U	Limited	Genetic Variation	[7]
Brugada syndrome 7	DISTWTOD	Limited	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 regulatory subunit beta-3 (SCN3B).	[9]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Sodium channel regulatory subunit beta-3 (SCN3B).	[10]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Sodium channel regulatory subunit beta-3 (SCN3B).	[11]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Sodium channel regulatory subunit beta-3 (SCN3B).	[12]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Sodium channel regulatory subunit beta-3 (SCN3B).	[13]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Sodium channel regulatory subunit beta-3 (SCN3B).	[14]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Sodium channel regulatory subunit beta-3 (SCN3B).	[15]
Folic acid	DMEMBJC	Approved	Folic acid decreases the expression of Sodium channel regulatory subunit beta-3 (SCN3B).	[17]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Sodium channel regulatory subunit beta-3 (SCN3B).	[19]
Manganese	DMKT129	Investigative	Manganese increases the expression of Sodium channel regulatory subunit beta-3 (SCN3B).	[20]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Fulvestrant	DM0YZC6	Approved	Fulvestrant decreases the methylation of Sodium channel regulatory subunit beta-3 (SCN3B).	[16]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Sodium channel regulatory subunit beta-3 (SCN3B).	[18]

References

• [1] Postmortem genetic screening for the identification, verification, and reporting of genetic variants contributing to the sudden death of the young.Genome Res. 2016 Sep;26(9):1170-7. doi: 10.1101/gr.195800.115. Epub 2016 Jul 19.
• [2] Identification of novel gene and pathway targets for human epilepsy treatment.Biol Res. 2016 Jan 7;49:3. doi: 10.1186/s40659-015-0060-5.
• [3] Loss-of-function mutation of the SCN3B-encoded sodium channel {beta}3 subunit associated with a case of idiopathic ventricular fibrillation.Cardiovasc Res. 2010 Jun 1;86(3):392-400. doi: 10.1093/cvr/cvp417. Epub 2009 Dec 30.
• [4] Functional dominant-negative mutation of sodium channel subunit gene SCN3B associated with atrial fibrillation in a Chinese GeneID population. Biochem Biophys Res Commun. 2010 Jul 16;398(1):98-104. doi: 10.1016/j.bbrc.2010.06.042. Epub 2010 Jun 15.
• [5] 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.
• [6] Embryonic type Na(+) channel -subunit, SCN3B masks the disease phenotype of Brugada syndrome.Sci Rep. 2016 Sep 28;6:34198. doi: 10.1038/srep34198.
• [7] Significant association of rare variant p.Gly8Ser in cardiac sodium channel 4-subunit SCN4B with atrial fibrillation.Ann Hum Genet. 2019 Jul;83(4):239-248. doi: 10.1111/ahg.12305. Epub 2019 Mar 1.
• [8] 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.
• [9] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [10] 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.
• [11] 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.
• [12] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [13] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [14] p53 hypersensitivity is the predominant mechanism of the unique responsiveness of testicular germ cell tumor (TGCT) cells to cisplatin. PLoS One. 2011 Apr 21;6(4):e19198. doi: 10.1371/journal.pone.0019198.
• [15] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [16] 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.
• [17] Folic acid supplementation dysregulates gene expression in lymphoblastoid cells--implications in nutrition. Biochem Biophys Res Commun. 2011 Sep 9;412(4):688-92. doi: 10.1016/j.bbrc.2011.08.027. Epub 2011 Aug 16.
• [18] 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.
• [19] 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.
• [20] Gene expression profiling of human primary astrocytes exposed to manganese chloride indicates selective effects on several functions of the cells. Neurotoxicology. 2007 May;28(3):478-89.