Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTFAHJ38)

• DOT Name: Sodium channel subunit beta-2 (SCN2B)
• Gene Name: SCN2B
• Related Disease:
  Epilepsy
  Charcot-Marie-Tooth disease type 4B1
  Dilated cardiomyopathy 1A
  Otitis media
  Atrial fibrillation, familial, 14
  Brugada syndrome
  Familial atrial fibrillation
  Brugada syndrome 1
  Conduction system disorder
  Sinoatrial node disorder
  Atrial fibrillation
• UniProt ID: SCN2B_HUMAN
• PDB ID: 5FDY; 5FEB; 6J8E; 6J8G; 6J8H; 6J8I; 6J8J; 6VRR; 7W77; 7W7F; 7W9K; 7W9L; 7W9M; 7W9P; 7W9T; 7XM9; 7XMF; 7XMG; 7XVE; 7XVF; 8G1A; 8GZ1; 8GZ2; 8I5B; 8I5G; 8I5X; 8I5Y; 8S9B; 8S9C; 8THG; 8THH
• Pfam ID: PF07686
• Sequence:
  MHRDAWLPRPAFSLTGLSLFFSLVPPGRSMEVTVPATLNVLNGSDARLPCTFNSCYTVNH
  KQFSLNWTYQECNNCSEEMFLQFRMKIINLKLERFQDRVEFSGNPSKYDVSVMLRNVQPE
  DEGIYNCYIMNPPDRHRGHGKIHLQVLMEEPPERDSTVAVIVGASVGGFLAVVILVLMVV
  KCVRRKKEQKLSTDDLKTEEEGKTDGEGNPDDGAK
• Function: Crucial in the assembly, expression, and functional modulation of the heterotrimeric complex of the sodium channel. The subunit beta-2 causes an increase in the plasma membrane surface area and in its folding into microvilli. Interacts with TNR may play a crucial role in clustering and regulation of activity of sodium channels at nodes of Ranvier.
• Tissue Specificity: Brain specific.
• 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

11 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Epilepsy	DISBB28L	Definitive	Biomarker	[1]
Charcot-Marie-Tooth disease type 4B1	DISSXR87	Strong	Genetic Variation	[2]
Dilated cardiomyopathy 1A	DIS0RK9Z	Strong	Altered Expression	[3]
Otitis media	DISGZDUO	Strong	Biomarker	[4]
Atrial fibrillation, familial, 14	DISAODPR	Moderate	Autosomal dominant	[5]
Brugada syndrome	DISSGN0E	Supportive	Autosomal dominant	[6]
Familial atrial fibrillation	DISL4AGF	Supportive	Autosomal dominant	[7]
Brugada syndrome 1	DISKBA7V	Disputed	Autosomal dominant	[8]
Conduction system disorder	DISED5HG	Disputed	Biomarker	[9]
Sinoatrial node disorder	DISYJI6J	Disputed	Biomarker	[9]
Atrial fibrillation	DIS15W6U	Limited	Genetic Variation	[10]

9 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 subunit beta-2 (SCN2B).	[11]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Sodium channel subunit beta-2 (SCN2B).	[12]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil affects the expression of Sodium channel subunit beta-2 (SCN2B).	[13]
Mitoxantrone	DMM39BF	Approved	Mitoxantrone decreases the expression of Sodium channel subunit beta-2 (SCN2B).	[12]
Daunorubicin	DMQUSBT	Approved	Daunorubicin decreases the expression of Sodium channel subunit beta-2 (SCN2B).	[12]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Sodium channel subunit beta-2 (SCN2B).	[14]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Sodium channel subunit beta-2 (SCN2B).	[15]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Sodium channel subunit beta-2 (SCN2B).	[17]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Sodium channel subunit beta-2 (SCN2B).	[18]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Sodium channel subunit beta-2 (SCN2B).	[16]

References

• [1] Case-control association study of polymorphisms in the voltage-gated sodium channel genes SCN1A, SCN2A, SCN3A, SCN1B, and SCN2B and epilepsy.Hum Genet. 2014 May;133(5):651-9. doi: 10.1007/s00439-013-1405-1. Epub 2013 Dec 13.
• [2] Exclusion of the SCN2B gene as candidate for CMT4B.Eur J Hum Genet. 1998 Nov-Dec;6(6):629-34. doi: 10.1038/sj.ejhg.5200220.
• [3] Differential gene expression of cardiac ion channels in human dilated cardiomyopathy.PLoS One. 2013 Dec 5;8(12):e79792. doi: 10.1371/journal.pone.0079792. eCollection 2013.
• [4] Suppression of epithelial ion transport transcripts during pneumococcal acute otitis media in the rat.Acta Otolaryngol. 2002 Jul;122(5):488-94. doi: 10.1080/00016480260092273.
• [5] 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.
• [6] A missense mutation in the sodium channel 2 subunit reveals SCN2B as a new candidate gene for Brugada syndrome. Hum Mutat. 2013 Jul;34(7):961-6. doi: 10.1002/humu.22328. Epub 2013 Apr 29.
• [7] Mutations in sodium channel 1- and 2-subunits associated with atrial fibrillation. Circ Arrhythm Electrophysiol. 2009 Jun;2(3):268-75. doi: 10.1161/CIRCEP.108.779181. Epub 2009 Mar 6.
• [8] 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.
• [9] Scn2b Deletion in Mice Results in Ventricular and Atrial Arrhythmias.Circ Arrhythm Electrophysiol. 2016 Dec;9(12):e003923. doi: 10.1161/CIRCEP.116.003923.
• [10] 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.
• [11] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [12] Identification of genomic biomarkers for anthracycline-induced cardiotoxicity in human iPSC-derived cardiomyocytes: an in vitro repeated exposure toxicity approach for safety assessment. Arch Toxicol. 2016 Nov;90(11):2763-2777.
• [13] Multi-level gene expression profiles affected by thymidylate synthase and 5-fluorouracil in colon cancer. BMC Genomics. 2006 Apr 3;7:68. doi: 10.1186/1471-2164-7-68.
• [14] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [15] 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.
• [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] 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.
• [18] 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.