Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTGD78J3)

• DOT Name: Sodium channel subunit beta-1 (SCN1B)
• Gene Name: SCN1B
• Related Disease:
  Absence epilepsy
  Brugada syndrome 5
  Generalized epilepsy with febrile seizures plus
  Generalized epilepsy with febrile seizures plus, type 1
  Infantile spasm
  Temporal lobe epilepsy
  Amelogenesis imperfecta type 1G
  Arrhythmia
  Benign neonatal seizures
  Childhood epilepsy with centrotemporal spikes
  Developmental and epileptic encephalopathy, 52
  Epilepsy
  Epilepsy syndrome
  Infantile epileptic-dyskinetic encephalopathy
  Non-insulin dependent diabetes
  Paroxysmal extreme pain disorder
  Seizures, benign familial neonatal, 2
  Obsolete Dravet syndrome
  Progressive familial heart block
  Brugada syndrome
  Brugada syndrome 1
  Conduction system disorder
  Progressive familial heart block, type 1A
  Sinoatrial node disorder
  Atrial fibrillation
  Atrial fibrillation, familial, 13
  Breast cancer
  Breast carcinoma
  Hirschsprung disease
  Long QT syndrome
• UniProt ID: SCN1B_HUMAN
• PDB ID: 6AGF; 6J8G; 6J8H; 6J8I; 6J8J; 7W77; 7W7F; 7W9K; 7W9L; 7W9M; 7W9P; 7W9T; 7XM9; 7XMF; 7XMG; 7XVE; 7XVF; 8FHD; 8G1A; 8GZ1; 8GZ2; 8I5B; 8I5G; 8I5X; 8I5Y; 8J4F; 8S9B; 8S9C; 8THG; 8THH
• Pfam ID: PF07686
• Sequence:
  MGRLLALVVGAALVSSACGGCVEVDSETEAVYGMTFKILCISCKRRSETNAETFTEWTFR
  QKGTEEFVKILRYENEVLQLEEDERFEGRVVWNGSRGTKDLQDLSIFITNVTYNHSGDYE
  CHVYRLLFFENYEHNTSVVKKIHIEVVDKANRDMASIVSEIMMYVLIVVLTIWLVAEMIY
  CYKKIAAATETAAQENASEYLAITSESKENCTGVQVAE
• Function: Regulatory subunit of multiple voltage-gated sodium channel complexes that play important roles in excitable membranes in brain, heart and skeletal muscle. Enhances the presence of the pore-forming alpha subunit at the cell surface and modulates channel gating characteristics and the rate of channel inactivation. Modulates the activity of multiple pore-forming alpha subunits, such as SCN1A, SCN2A, SCN3A, SCN4A, SCN5A and SCN10A; [Isoform 2]: Cell adhesion molecule that plays a critical role in neuronal migration and pathfinding during brain development. Stimulates neurite outgrowth. Has no regulatory function on the SCN2A sodium channel complex.
• Tissue Specificity: The overall expression of isoform 1 and isoform 2 is very similar. Isoform 1 is abundantly expressed in skeletal muscle, heart and brain. Isoform 2 is highly expressed in brain and skeletal muscle and present at a very low level in heart, placenta, lung, liver, kidney and pancreas. In brain, isoform 2 is most abundant in the cerebellum, followed by the cerebral cortex and occipital lobe, while isoform 1 levels are higher in the cortex compared to the cerebellum. Isoform 2 is expressed in many regions of the brain, including cerebellar Purkinje cells, cortex pyramidal neurons and many of the neuronal fibers throughout the brain (at protein level). Also detected in dorsal root ganglion, in fibers of the spinal nerve and in cortical neurons and their processes (at protein level).
• 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

30 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Absence epilepsy	DISJPOUD	Definitive	Genetic Variation	[1]
Brugada syndrome 5	DIS0WTRT	Definitive	Autosomal dominant	[2]
Generalized epilepsy with febrile seizures plus	DISJE0UU	Definitive	Autosomal dominant	[3]
Generalized epilepsy with febrile seizures plus, type 1	DISEFU4U	Definitive	Autosomal dominant	[4]
Infantile spasm	DISZSKDG	Definitive	Autosomal recessive	[3]
Temporal lobe epilepsy	DISNOPXX	Definitive	Genetic Variation	[2]
Amelogenesis imperfecta type 1G	DISS8U5Q	Strong	Genetic Variation	[5]
Arrhythmia	DISFF2NI	Strong	Genetic Variation	[6]
Benign neonatal seizures	DISWNBHF	Strong	Biomarker	[7]
Childhood epilepsy with centrotemporal spikes	DISKT2L5	Strong	CausalMutation	[8]
Developmental and epileptic encephalopathy, 52	DIS03XMZ	Strong	Autosomal recessive	[9]
Epilepsy	DISBB28L	Strong	Genetic Variation	[10]
Epilepsy syndrome	DISLYXJ3	Strong	Genetic Variation	[11]
Infantile epileptic-dyskinetic encephalopathy	DISD2ZNC	Strong	Genetic Variation	[12]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Biomarker	[13]
Paroxysmal extreme pain disorder	DISNHO6B	Strong	Biomarker	[14]
Seizures, benign familial neonatal, 2	DISLZ3VQ	Strong	Biomarker	[14]
Obsolete Dravet syndrome	DISM4LMK	Supportive	Autosomal dominant	[9]
Progressive familial heart block	DISNEF3B	Supportive	Autosomal dominant	[15]
Brugada syndrome	DISSGN0E	Disputed	Biomarker	[16]
Brugada syndrome 1	DISKBA7V	Disputed	Autosomal dominant	[3]
Conduction system disorder	DISED5HG	Disputed	Biomarker	[17]
Progressive familial heart block, type 1A	DISUPY6A	Disputed	GermlineCausalMutation	[15]
Sinoatrial node disorder	DISYJI6J	Disputed	Biomarker	[17]
Atrial fibrillation	DIS15W6U	Limited	Genetic Variation	[18]
Atrial fibrillation, familial, 13	DISHUYSG	Limited	Unknown	[19]
Breast cancer	DIS7DPX1	Limited	Altered Expression	[20]
Breast carcinoma	DIS2UE88	Limited	Altered Expression	[20]
Hirschsprung disease	DISUUSM1	Limited	Altered Expression	[21]
Long QT syndrome	DISMKWS3	Limited	Genetic Variation	[22]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Phenytoin	DMNOKBV	Approved	Sodium channel subunit beta-1 (SCN1B) decreases the response to substance of Phenytoin.	[30]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Sodium channel subunit beta-1 (SCN1B).	[23]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Sodium channel subunit beta-1 (SCN1B).	[24]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Sodium channel subunit beta-1 (SCN1B).	[25]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Sodium channel subunit beta-1 (SCN1B).	[26]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Sodium channel subunit beta-1 (SCN1B).	[26]
Aspirin	DM672AH	Approved	Aspirin increases the expression of Sodium channel subunit beta-1 (SCN1B).	[27]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Sodium channel subunit beta-1 (SCN1B).	[28]

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 affects the methylation of Sodium channel subunit beta-1 (SCN1B).	[29]

References

• [1] A deletion in SCN1B is associated with febrile seizures and early-onset absence epilepsy. Neurology. 2003 Sep 23;61(6):854-6. doi: 10.1212/01.wnl.0000080362.55784.1c.
• [2] Temporal lobe epilepsy and GEFS+ phenotypes associated with SCN1B mutations. Brain. 2007 Jan;130(Pt 1):100-9. doi: 10.1093/brain/awl272. Epub 2006 Oct 4.
• [3] 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.
• [4] Febrile seizures and generalized epilepsy associated with a mutation in the Na+-channel beta1 subunit gene SCN1B. Nat Genet. 1998 Aug;19(4):366-70. doi: 10.1038/1252.
• [5] SCN1B mutations that affect their association with Kv4.3 underlie early repolarization syndrome.J Cell Mol Med. 2018 Nov;22(11):5639-5647. doi: 10.1111/jcmm.13839. Epub 2018 Aug 30.
• [6] SCN1B gene variants in Brugada Syndrome: a study of 145 SCN5A-negative patients.Sci Rep. 2014 Sep 25;4:6470. doi: 10.1038/srep06470.
• [7] Study of the voltage-gated sodium channel beta 1 subunit gene (SCN1B) in the benign familial infantile convulsions syndrome (BFIC).Hum Mutat. 2000;16(2):139-42. doi: 10.1002/1098-1004(200008)16:2<139::AID-HUMU6>3.0.CO;2-J.
• [8] Exome-wide analysis of mutational burden in patients with typical and atypical Rolandic epilepsy.Eur J Hum Genet. 2018 Feb;26(2):258-264. doi: 10.1038/s41431-017-0034-x. Epub 2018 Jan 22.
• [9] A functional null mutation of SCN1B in a patient with Dravet syndrome. J Neurosci. 2009 Aug 26;29(34):10764-78. doi: 10.1523/JNEUROSCI.2475-09.2009.
• [10] Mutations in SCN3A cause early infantile epileptic encephalopathy. Ann Neurol. 2018 Apr;83(4):703-717. doi: 10.1002/ana.25188. Epub 2018 Mar 30.
• [11] Confirming the recessive inheritance of SCN1B mutations in developmental epileptic encephalopathy. Clin Genet. 2017 Sep;92(3):327-331. doi: 10.1111/cge.12999. Epub 2017 Apr 19.
• [12] SCN1B-linked early infantile developmental and epileptic encephalopathy.Ann Clin Transl Neurol. 2019 Dec;6(12):2354-2367. doi: 10.1002/acn3.50921. Epub 2019 Nov 11.
• [13] Shortening and intracellular Ca2+ in ventricular myocytes and expression of genes encoding cardiac muscle proteins in early onset type 2 diabetic Goto-Kakizaki rats.Exp Physiol. 2012 Dec;97(12):1281-91. doi: 10.1113/expphysiol.2012.066639. Epub 2012 May 11.
• [14] Molecular genetics of infantile nervous system channelopathies.Early Hum Dev. 2006 Dec;82(12):775-9. doi: 10.1016/j.earlhumdev.2006.09.013. Epub 2006 Oct 17.
• [15] Sodium channel 1 subunit mutations associated with Brugada syndrome and cardiac conduction disease in humans. J Clin Invest. 2008 Jun;118(6):2260-8. doi: 10.1172/JCI33891.
• [16] Sudden unexpected death in GEFS+ families with sodium channel pathogenic variants.Epilepsy Res. 2019 Feb;150:66-69. doi: 10.1016/j.eplepsyres.2019.01.009. Epub 2019 Jan 14.
• [17] Cardiac conduction defects and Brugada syndrome: A family with overlap syndrome carrying a nonsense SCN5A mutation.J Arrhythm. 2017 Feb;33(1):35-39. doi: 10.1016/j.joa.2016.05.007. Epub 2016 Jul 2.
• [18] 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.
• [19] 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.
• [20] The sodium channel 1 subunit mediates outgrowth of neurite-like processes on breast cancer cells and promotes tumour growth and metastasis.Int J Cancer. 2014 Nov 15;135(10):2338-51. doi: 10.1002/ijc.28890. Epub 2014 Apr 26.
• [21] Abnormal Scn1b and Fxyd1 gene expression in the pulled-through ganglionic colon may influence functional outcome in patients with Hirschsprung's disease.Pediatr Surg Int. 2019 Jan;35(1):9-14. doi: 10.1007/s00383-018-4370-x. Epub 2018 Nov 1.
• [22] A missense mutation in the sodium channel 1b subunit reveals SCN1B as a susceptibility gene underlying long QT syndrome.Heart Rhythm. 2014 Jul;11(7):1202-9. doi: 10.1016/j.hrthm.2014.03.044. Epub 2014 Mar 21.
• [23] 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.
• [24] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [25] 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.
• [26] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [27] Expression profile analysis of colon cancer cells in response to sulindac or aspirin. Biochem Biophys Res Commun. 2002 Mar 29;292(2):498-512.
• [28] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [29] Effect of aflatoxin B(1), benzo[a]pyrene, and methapyrilene on transcriptomic and epigenetic alterations in human liver HepaRG cells. Food Chem Toxicol. 2018 Nov;121:214-223. doi: 10.1016/j.fct.2018.08.034. Epub 2018 Aug 26.
• [30] An epilepsy mutation in the beta1 subunit of the voltage-gated sodium channel results in reduced channel sensitivity to phenytoin. Epilepsy Res. 2005 May;64(3):77-84. doi: 10.1016/j.eplepsyres.2005.03.003.