Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT3JSUWO)

• DOT Name: Sodium channel subunit beta-4 (SCN4B)
• Gene Name: SCN4B
• Related Disease:
  Advanced cancer
  Breast cancer
  Breast carcinoma
  Bronchopulmonary dysplasia
  Familial atrial fibrillation
  Long QT syndrome
  Atrial fibrillation
  Brugada syndrome
  Familial long QT syndrome
  Long QT syndrome 10
  Ventricular tachycardia
• UniProt ID: SCN4B_HUMAN
• PDB ID: 4MZ2; 4MZ3; 5XAW; 6VSV; 7DTD
• Pfam ID: PF07686
• Sequence:
  MPGAGDGGKAPARWLGTGLLGLFLLPVTLSLEVSVGKATDIYAVNGTEILLPCTFSSCFG
  FEDLHFRWTYNSSDAFKILIEGTVKNEKSDPKVTLKDDDRITLVGSTKEKMNNISIVLRD
  LEFSDTGKYTCHVKNPKENNLQHHATIFLQVVDRLEEVDNTVTLIILAVVGGVIGLLILI
  LLIKKLIIFILKKTREKKKECLVSSSGNDNTENGLPGSKAEEKPPSKV
• Function: Modulates channel gating kinetics. Causes negative shifts in the voltage dependence of activation of certain alpha sodium channels, but does not affect the voltage dependence of inactivation. Modulates the susceptibility of the sodium channel to inhibition by toxic peptides from spider, scorpion, wasp and sea anemone venom.
• Tissue Specificity: Expressed at a high level in dorsal root ganglia, at a lower level in brain, spinal cord, skeletal muscle and heart. Expressed in the atrium.
• KEGG Pathway: Adrenergic sig.ling in cardiomyocytes (hsa04261)
• 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
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[1]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[1]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[1]
Bronchopulmonary dysplasia	DISO0BY5	Strong	Altered Expression	[2]
Familial atrial fibrillation	DISL4AGF	Supportive	Autosomal dominant	[3]
Long QT syndrome	DISMKWS3	Disputed	Autosomal dominant	[4]
Atrial fibrillation	DIS15W6U	Limited	Genetic Variation	[5]
Brugada syndrome	DISSGN0E	Limited	Genetic Variation	[6]
Familial long QT syndrome	DISRNNCY	Limited	Biomarker	[7]
Long QT syndrome 10	DISH4OHI	Limited	Unknown	[8]
Ventricular tachycardia	DISIBXJ3	Limited	Genetic Variation	[9]

11 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-4 (SCN4B).	[10]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Sodium channel subunit beta-4 (SCN4B).	[11]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Sodium channel subunit beta-4 (SCN4B).	[12]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Sodium channel subunit beta-4 (SCN4B).	[13]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Sodium channel subunit beta-4 (SCN4B).	[14]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Sodium channel subunit beta-4 (SCN4B).	[14]
Etoposide	DMNH3PG	Approved	Etoposide increases the expression of Sodium channel subunit beta-4 (SCN4B).	[15]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Sodium channel subunit beta-4 (SCN4B).	[14]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Sodium channel subunit beta-4 (SCN4B).	[17]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Sodium channel subunit beta-4 (SCN4B).	[18]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde increases the expression of Sodium channel subunit beta-4 (SCN4B).	[19]

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-4 (SCN4B).	[16]

References

• [1] SCN4B acts as a metastasis-suppressor gene preventing hyperactivation of cell migration in breast cancer.Nat Commun. 2016 Dec 5;7:13648. doi: 10.1038/ncomms13648.
• [2] Transcriptomic Analysis of Induced Pluripotent Stem Cells Derived from Patients with Bipolar Disorder from an Old Order Amish Pedigree.PLoS One. 2015 Nov 10;10(11):e0142693. doi: 10.1371/journal.pone.0142693. eCollection 2015.
• [3] Mutations of the SCN4B-encoded sodium channel 4 subunit in familial atrial fibrillation. Int J Mol Med. 2013 Jul;32(1):144-50. doi: 10.3892/ijmm.2013.1355. Epub 2013 Apr 22.
• [4] 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.
• [5] 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.
• [6] Contribution of Cardiac Sodium Channel -Subunit Variants to Brugada Syndrome.Circ J. 2015;79(10):2118-29. doi: 10.1253/circj.CJ-15-0164. Epub 2015 Jul 15.
• [7] SCN4B-encoded sodium channel beta4 subunit in congenital long-QT syndrome. Circulation. 2007 Jul 10;116(2):134-42. doi: 10.1161/CIRCULATIONAHA.106.659086. Epub 2007 Jun 25.
• [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] Identification of rare variants in cardiac sodium channel 4-subunit gene SCN4B associated with ventricular tachycardia.Mol Genet Genomics. 2019 Aug;294(4):1059-1071. doi: 10.1007/s00438-019-01567-7. Epub 2019 Apr 17.
• [10] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [11] Retinoic acid receptor alpha amplifications and retinoic acid sensitivity in breast cancers. Clin Breast Cancer. 2013 Oct;13(5):401-8.
• [12] Functional cardiotoxicity assessment of cosmetic compounds using human-induced pluripotent stem cell-derived cardiomyocytes. Arch Toxicol. 2018 Jan;92(1):371-381.
• [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] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [15] Cell death mechanisms of the anti-cancer drug etoposide on human cardiomyocytes isolated from pluripotent stem cells. Arch Toxicol. 2018 Apr;92(4):1507-1524.
• [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.
• [19] Transcriptome profile analysis of saturated aliphatic aldehydes reveals carbon number-specific molecules involved in pulmonary toxicity. Chem Res Toxicol. 2014 Aug 18;27(8):1362-70.