Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTUO214Y)

• DOT Name: Potassium voltage-gated channel subfamily E member 2 (KCNE2)
• Synonyms: MinK-related peptide 1; Minimum potassium ion channel-related peptide 1; Potassium channel subunit beta MiRP1
• Gene Name: KCNE2
• Related Disease:
  Hepatocellular carcinoma
  Long QT syndrome 1
  Non-insulin dependent diabetes
  Sinoatrial node disorder
  Adenoma
  Advanced cancer
  Anemia
  Arrhythmia
  Arteriosclerosis
  Atherosclerosis
  Cardiac failure
  Catecholaminergic polymorphic ventricular tachycardia 1
  Congestive heart failure
  Coronary heart disease
  Familial long QT syndrome
  Gastric cancer
  Hypothyroidism
  Neoplasm
  Stomach cancer
  Obesity
  Ventricular fibrillation
  Familial atrial fibrillation
  Long QT syndrome
  Andersen-Tawil syndrome
  Atrial fibrillation
  Brugada syndrome
  Jervell and Lange-Nielsen syndrome
  Long QT syndrome 6
  Myocardial infarction
• UniProt ID: KCNE2_HUMAN
• PDB ID: 2M0Q
• Pfam ID: PF02060
• Sequence:
  MSTLSNFTQTLEDVFRRIFITYMDNWRQNTTAEQEALQAKVDAENFYYVILYLMVMIGMF
  SFIIVAILVSTVKSKRREHSNDPYHQYIVEDWQEKYKSQILNLEESKATIHENIGAAGFK
  MSP
• Function: Ancillary protein that assembles as a beta subunit with a voltage-gated potassium channel complex of pore-forming alpha subunits. Modulates the gating kinetics and enhances stability of the channel complex. Assembled with KCNB1 modulates the gating characteristics of the delayed rectifier voltage-dependent potassium channel KCNB1. Associated with KCNH2/HERG is proposed to form the rapidly activating component of the delayed rectifying potassium current in heart (IKr). May associate with KCNQ2 and/or KCNQ3 and modulate the native M-type current. May associate with HCN1 and HCN2 and increase potassium current. Interacts with KCNQ1; forms a heterooligomer complex leading to currents with an apparently instantaneous activation, a rapid deactivation process and a linear current-voltage relationship and decreases the amplitude of the outward current. KCNQ1-KCNE2 channel associates with Na(+)-coupled myo-inositol symporter in the apical membrane of choroid plexus epithelium and regulates the myo-inositol gradient between blood and cerebrospinal fluid with an impact on neuron excitability.
• Tissue Specificity: Highly expressed in brain, heart, skeletal muscle, pancreas, placenta, kidney, colon and thymus. A small but significant expression is found in liver, ovary, testis, prostate, small intestine and leukocytes. Very low expression, nearly undetectable, in lung and spleen.
• KEGG Pathway: Gastric acid secretion (hsa04971)
• Reactome Pathway:
  Phase 2 - plateau phase (R-HSA-5576893)
  Phase 3 - rapid repolarisation (R-HSA-5576890)

Molecular Interaction Atlas (MIA) of This DOT

29 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hepatocellular carcinoma	DIS0J828	Definitive	Biomarker	[1]
Long QT syndrome 1	DISXK5OU	Definitive	Genetic Variation	[2]
Non-insulin dependent diabetes	DISK1O5Z	Definitive	Altered Expression	[3]
Sinoatrial node disorder	DISYJI6J	Definitive	Genetic Variation	[4]
Adenoma	DIS78ZEV	Strong	Biomarker	[5]
Advanced cancer	DISAT1Z9	Strong	Genetic Variation	[6]
Anemia	DISTVL0C	Strong	Biomarker	[7]
Arrhythmia	DISFF2NI	Strong	Biomarker	[8]
Arteriosclerosis	DISK5QGC	Strong	Genetic Variation	[9]
Atherosclerosis	DISMN9J3	Strong	Genetic Variation	[9]
Cardiac failure	DISDC067	Strong	Biomarker	[10]
Catecholaminergic polymorphic ventricular tachycardia 1	DISKGB3F	Strong	Biomarker	[11]
Congestive heart failure	DIS32MEA	Strong	Biomarker	[10]
Coronary heart disease	DIS5OIP1	Strong	Biomarker	[12]
Familial long QT syndrome	DISRNNCY	Strong	Biomarker	[13]
Gastric cancer	DISXGOUK	Strong	Biomarker	[5]
Hypothyroidism	DISR0H6D	Strong	Biomarker	[14]
Neoplasm	DISZKGEW	Strong	Biomarker	[5]
Stomach cancer	DISKIJSX	Strong	Biomarker	[5]
Obesity	DIS47Y1K	moderate	Genetic Variation	[12]
Ventricular fibrillation	DIS7IN76	moderate	Genetic Variation	[15]
Familial atrial fibrillation	DISL4AGF	Supportive	Autosomal dominant	[16]
Long QT syndrome	DISMKWS3	Disputed	Autosomal dominant	[17]
Andersen-Tawil syndrome	DIS3IWZ7	Limited	Biomarker	[18]
Atrial fibrillation	DIS15W6U	Limited	Genetic Variation	[19]
Brugada syndrome	DISSGN0E	Limited	Biomarker	[20]
Jervell and Lange-Nielsen syndrome	DISGCX89	Limited	Biomarker	[2]
Long QT syndrome 6	DISSE4S5	Limited	Autosomal dominant	[21]
Myocardial infarction	DIS655KI	Limited	Genetic Variation	[22]

3 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 Potassium voltage-gated channel subfamily E member 2 (KCNE2).	[23]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Potassium voltage-gated channel subfamily E member 2 (KCNE2).	[25]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Potassium voltage-gated channel subfamily E member 2 (KCNE2).	[28]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Potassium voltage-gated channel subfamily E member 2 (KCNE2).	[24]
Phenobarbital	DMXZOCG	Approved	Phenobarbital increases the expression of Potassium voltage-gated channel subfamily E member 2 (KCNE2).	[26]
Dexamethasone	DMMWZET	Approved	Dexamethasone affects the expression of Potassium voltage-gated channel subfamily E member 2 (KCNE2).	[27]

References

• [1] miR-584-5p regulates hepatocellular carcinoma cell migration and invasion through targeting KCNE2.Mol Genet Genomic Med. 2019 Jun;7(6):e702. doi: 10.1002/mgg3.702. Epub 2019 May 1.
• [2] Molecular genetic analysis of long QT syndrome in Norway indicating a high prevalence of heterozygous mutation carriers.Scand J Clin Lab Invest. 2008;68(5):362-8. doi: 10.1080/00365510701765643.
• [3] Kcne2 deletion impairs insulin secretion and causes type 2 diabetes mellitus.FASEB J. 2017 Jun;31(6):2674-2685. doi: 10.1096/fj.201601347. Epub 2017 Mar 9.
• [4] Pacemaker activity of the human sinoatrial node: effects of HCN4 mutations on the hyperpolarization-activated current.Europace. 2014 Mar;16(3):384-95. doi: 10.1093/europace/eut348.
• [5] Targeted deletion of Kcne2 causes gastritis cystica profunda and gastric neoplasia.PLoS One. 2010 Jul 6;5(7):e11451. doi: 10.1371/journal.pone.0011451.
• [6] Cancer risk susceptibility loci in a Swedish population.Oncotarget. 2017 Nov 25;8(66):110300-110310. doi: 10.18632/oncotarget.22687. eCollection 2017 Dec 15.
• [7] Disruption of the potassium channel regulatory subunit KCNE2 causes iron-deficient anemia.Exp Hematol. 2014 Dec;42(12):1053-8.e1. doi: 10.1016/j.exphem.2014.07.269. Epub 2014 Aug 12.
• [8] A novel transgenic rabbit model with reduced repolarization reserve: long QT syndrome caused by a dominant-negative mutation of the KCNE1 gene.Br J Pharmacol. 2016 Jun;173(12):2046-61. doi: 10.1111/bph.13500. Epub 2016 May 19.
• [9] Kcne2 deletion promotes atherosclerosis and diet-dependent sudden death.J Mol Cell Cardiol. 2015 Oct;87:148-51. doi: 10.1016/j.yjmcc.2015.08.013. Epub 2015 Aug 22.
• [10] LCZ696 Therapy Reduces Ventricular Tachyarrhythmia Inducibility in a Myocardial Infarction-Induced Heart Failure Rat Model.Cardiovasc Ther. 2019 Jul 1;2019:6032631. doi: 10.1155/2019/6032631. eCollection 2019.
• [11] Genetic screening in sudden cardiac death in the young can save future lives.Int J Legal Med. 2016 Jan;130(1):59-66. doi: 10.1007/s00414-015-1237-8. Epub 2015 Jul 31.
• [12] The association of obesity and coronary artery disease genes with response to SSRIs treatment in major depression.J Neural Transm (Vienna). 2019 Jan;126(1):35-45. doi: 10.1007/s00702-018-01966-x. Epub 2019 Jan 4.
• [13] Four potassium channel mutations account for 73% of the genetic spectrum underlying long-QT syndrome (LQTS) and provide evidence for a strong founder effect in Finland.Ann Med. 2004;36 Suppl 1:53-63. doi: 10.1080/17431380410032689.
• [14] The KCNQ1-KCNE2 K?channel is required for adequate thyroid I?uptake.FASEB J. 2012 Aug;26(8):3252-9. doi: 10.1096/fj.12-206110. Epub 2012 May 1.
• [15] MiRP1 forms IKr potassium channels with HERG and is associated with cardiac arrhythmia. Cell. 1999 Apr 16;97(2):175-87. doi: 10.1016/s0092-8674(00)80728-x.
• [16] Identification of a KCNE2 gain-of-function mutation in patients with familial atrial fibrillation. Am J Hum Genet. 2004 Nov;75(5):899-905. doi: 10.1086/425342. Epub 2004 Sep 13.
• [17] 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.
• [18] Genotypic heterogeneity and phenotypic mimicry among unrelated patients referred for catecholaminergic polymorphic ventricular tachycardia genetic testing.Heart Rhythm. 2006 Jul;3(7):800-5. doi: 10.1016/j.hrthm.2006.03.025. Epub 2006 Mar 28.
• [19] The research of ion channel-related gene polymorphisms with atrial fibrillation in the Chinese Han population.Mol Genet Genomic Med. 2019 Aug;7(8):e835. doi: 10.1002/mgg3.835. Epub 2019 Jul 4.
• [20] Postmortem molecular analysis of KCNQ1, KCNH2, KCNE1 and KCNE2 genes in sudden unexplained nocturnal death syndrome in the Chinese Han population.Forensic Sci Int. 2013 Sep 10;231(1-3):82-7. doi: 10.1016/j.forsciint.2013.04.020. Epub 2013 May 15.
• [21] The KCNE2 potassium channel ancillary subunit is essential for gastric acid secretion. J Biol Chem. 2006 Aug 18;281(33):23740-7. doi: 10.1074/jbc.M604155200. Epub 2006 Jun 5.
• [22] A genome-wide association study reveals susceptibility loci for myocardial infarction/coronary artery disease in Saudi Arabs.Atherosclerosis. 2016 Feb;245:62-70. doi: 10.1016/j.atherosclerosis.2015.11.019. Epub 2015 Nov 22.
• [23] 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.
• [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] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [26] Dose- and time-dependent effects of phenobarbital on gene expression profiling in human hepatoma HepaRG cells. Toxicol Appl Pharmacol. 2009 Feb 1;234(3):345-60.
• [27] Neuronal and cardiac toxicity of pharmacological compounds identified through transcriptomic analysis of human pluripotent stem cell-derived embryoid bodies. Toxicol Appl Pharmacol. 2021 Dec 15;433:115792. doi: 10.1016/j.taap.2021.115792. Epub 2021 Nov 3.
• [28] 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.