Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT3CXQJT)

• DOT Name: Potassium voltage-gated channel subfamily KQT member 2 (KCNQ2)
• Synonyms: KQT-like 2; Neuroblastoma-specific potassium channel subunit alpha KvLQT2; Voltage-gated potassium channel subunit Kv7.2
• Gene Name: KCNQ2
• Related Disease:
  Complex neurodevelopmental disorder
  Developmental and epileptic encephalopathy, 7
  Neonatal encephalopathy with non-epileptic myoclonus
  Neonatal-onset developmental and epileptic encephalopathy
  Seizures, benign familial neonatal, 1
  Seizures, benign familial neonatal, 2
  Benign familial infantile epilepsy
  Benign neonatal seizures
  Malignant migrating partial seizures of infancy
  Obsolete benign familial neonatal-infantile seizures
• UniProt ID: KCNQ2_HUMAN
• PDB ID: 5J03; 6FEG; 6FEH; 7CR0; 7CR1; 7CR2; 7CR3; 7CR4; 7CR7; 8IZY; 8J00; 8J03; 8J04; 8J05
• Pfam ID: PF00520 ; PF16642 ; PF03520 ; PF11956
• Sequence:
  MVQKSRNGGVYPGPSGEKKLKVGFVGLDPGAPDSTRDGALLIAGSEAPKRGSILSKPRAG
  GAGAGKPPKRNAFYRKLQNFLYNVLERPRGWAFIYHAYVFLLVFSCLVLSVFSTIKEYEK
  SSEGALYILEIVTIVVFGVEYFVRIWAAGCCCRYRGWRGRLKFARKPFCVIDIMVLIASI
  AVLAAGSQGNVFATSALRSLRFLQILRMIRMDRRGGTWKLLGSVVYAHSKELVTAWYIGF
  LCLILASFLVYLAEKGENDHFDTYADALWWGLITLTTIGYGDKYPQTWNGRLLAATFTLI
  GVSFFALPAGILGSGFALKVQEQHRQKHFEKRRNPAAGLIQSAWRFYATNLSRTDLHSTW
  QYYERTVTVPMYSSQTQTYGASRLIPPLNQLELLRNLKSKSGLAFRKDPPPEPSPSKGSP
  CRGPLCGCCPGRSSQKVSLKDRVFSSPRGVAAKGKGSPQAQTVRRSPSADQSLEDSPSKV
  PKSWSFGDRSRARQAFRIKGAASRQNSEEASLPGEDIVDDKSCPCEFVTEDLTPGLKVSI
  RAVCVMRFLVSKRKFKESLRPYDVMDVIEQYSAGHLDMLSRIKSLQSRVDQIVGRGPAIT
  DKDRTKGPAEAELPEDPSMMGRLGKVEKQVLSMEKKLDFLVNIYMQRMGIPPTETEAYFG
  AKEPEPAPPYHSPEDSREHVDRHGCIVKIVRSSSSTGQKNFSAPPAAPPVQCPPSTSWQP
  QSHPRQGHGTSPVGDHGSLVRIPPPPAHERSLSAYGGGNRASMEFLRQEDTPGCRPPEGN
  LRDSDTSISIPSVDHEELERSFSGFSISQSKENLDALNSCYAAVAPCAKVRPYIAEGESD
  TDSDLCTPCGPPPRSATGEGPFGDVGWAGPRK
• Function: Associates with KCNQ3 to form a potassium channel with essentially identical properties to the channel underlying the native M-current, a slowly activating and deactivating potassium conductance which plays a critical role in determining the subthreshold electrical excitability of neurons as well as the responsiveness to synaptic inputs. Therefore, it is important in the regulation of neuronal excitability. KCNQ2/KCNQ3 current is blocked by linopirdine and XE991, and activated by the anticonvulsant retigabine. As the native M-channel, the potassium channel composed of KCNQ2 and KCNQ3 is also suppressed by activation of the muscarinic acetylcholine receptor CHRM1. KCNQ2-KCNQ3 channel is selectively permeable to other cations besides potassium, in decreasing order of affinity K(+) > Rb(+) > Cs(+) > Na(+). Associates with Na(+)-coupled myo-inositol symporter SLC5A3 forming a coregulatory complex that alters ion selectivity, increasing Na(+) and Cs(+) permeation relative to K(+) permeation.
• Tissue Specificity: In adult and fetal brain. Highly expressed in areas containing neuronal cell bodies, low in spinal cord and corpus callosum. Isoform 2 is preferentially expressed in differentiated neurons. Isoform 6 is prominent in fetal brain, undifferentiated neuroblastoma cells and brain tumors.
• KEGG Pathway: Cholinergic sy.pse (hsa04725)
• Reactome Pathway:
  Interaction between L1 and Ankyrins (R-HSA-445095)
  Voltage gated Potassium channels (R-HSA-1296072)

Molecular Interaction Atlas (MIA) of This DOT

10 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Complex neurodevelopmental disorder	DISB9AFI	Definitive	Autosomal dominant	[1]
Developmental and epileptic encephalopathy, 7	DIS9VGPW	Definitive	Autosomal dominant	[2]
Neonatal encephalopathy with non-epileptic myoclonus	DIS9V1LH	Definitive	Autosomal dominant	[1]
Neonatal-onset developmental and epileptic encephalopathy	DIS8837Y	Definitive	Autosomal dominant	[1]
Seizures, benign familial neonatal, 1	DIS2O53U	Definitive	Autosomal dominant	[3]
Seizures, benign familial neonatal, 2	DISLZ3VQ	Strong	Autosomal dominant	[4]
Benign familial infantile epilepsy	DISFYXOW	Supportive	Autosomal dominant	[5]
Benign neonatal seizures	DISWNBHF	Supportive	Autosomal dominant	[6]
Malignant migrating partial seizures of infancy	DISF2TRU	Supportive	Autosomal dominant	[7]
Obsolete benign familial neonatal-infantile seizures	DISQVTP9	Supportive	Autosomal dominant	[8]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Potassium voltage-gated channel subfamily KQT member 2 (KCNQ2).	[9]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Potassium voltage-gated channel subfamily KQT member 2 (KCNQ2).	[12]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Potassium voltage-gated channel subfamily KQT member 2 (KCNQ2).	[15]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Potassium voltage-gated channel subfamily KQT member 2 (KCNQ2).	[10]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Potassium voltage-gated channel subfamily KQT member 2 (KCNQ2).	[11]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of Potassium voltage-gated channel subfamily KQT member 2 (KCNQ2).	[13]
Retigabine	DMGNYIH	Approved	Retigabine affects the activity of Potassium voltage-gated channel subfamily KQT member 2 (KCNQ2).	[14]
BENZOYLENUREA	DMY5O1U	Investigative	BENZOYLENUREA increases the activity of Potassium voltage-gated channel subfamily KQT member 2 (KCNQ2).	[16]

References

• [1] 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.
• [2] Video/EEG findings in a KCNQ2 epileptic encephalopathy: a case report and revision of literature data. Epileptic Disord. 2013 Jun;15(2):158-65. doi: 10.1684/epd.2013.0578.
• [3] Structural and mutational analysis of KCNQ2, the major gene locus for benign familial neonatal convulsions. Hum Genet. 1999 Mar;104(3):234-40. doi: 10.1007/pl00008713.
• [4] KCNQ2 and KCNQ3 potassium channel genes in benign familial neonatal convulsions: expansion of the functional and mutation spectrum. Brain. 2003 Dec;126(Pt 12):2726-37. doi: 10.1093/brain/awg286. Epub 2003 Oct 8.
• [5] Clinical Practice Guidelines for Rare Diseases: The Orphanet Database. PLoS One. 2017 Jan 18;12(1):e0170365. doi: 10.1371/journal.pone.0170365. eCollection 2017.
• [6] KCNQ2-Related Disorders. 2010 Apr 27 [updated 2022 May 19]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews(?) [Internet]. Seattle (WA): University of Washington, Seattle; 1993C2024.
• [7] The Genetic Landscape of Epilepsy of Infancy with Migrating Focal Seizures. Ann Neurol. 2019 Dec;86(6):821-831. doi: 10.1002/ana.25619.
• [8] Genetic testing in benign familial epilepsies of the first year of life: clinical and diagnostic significance. Epilepsia. 2013 Mar;54(3):425-36. doi: 10.1111/epi.12089. Epub 2013 Jan 29.
• [9] 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.
• [10] 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.
• [11] 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.
• [12] 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.
• [13] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [14] The Sensorless Pore Module of Voltage-gated K+ Channel Family 7 Embodies the Target Site for the Anticonvulsant Retigabine. J Biol Chem. 2016 Feb 5;291(6):2931-7. doi: 10.1074/jbc.M115.683185. Epub 2015 Dec 1.
• [15] 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.
• [16] KCNQ2/3 openers show differential selectivity and site of action across multiple KCNQ channels. J Neurosci Methods. 2011 Aug 30;200(1):54-62. doi: 10.1016/j.jneumeth.2011.06.014. Epub 2011 Jun 23.