Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT29B58J)

• DOT Name: Potassium voltage-gated channel subfamily KQT member 4 (KCNQ4)
• Synonyms: KQT-like 4; Potassium channel subunit alpha KvLQT4; Voltage-gated potassium channel subunit Kv7.4
• Gene Name: KCNQ4
• Related Disease:
  Nonsyndromic genetic hearing loss
  Autosomal dominant nonsyndromic hearing loss 2A
  Autosomal dominant nonsyndromic hearing loss
• UniProt ID: KCNQ4_HUMAN
• PDB ID: 2OVC; 4GOW; 6N5W; 7BYL; 7BYM; 7BYN; 7VNP; 7VNQ; 7VNR
• Pfam ID: PF00520 ; PF03520
• Sequence:
  MAEAPPRRLGLGPPPGDAPRAELVALTAVQSEQGEAGGGGSPRRLGLLGSPLPPGAPLPG
  PGSGSGSACGQRSSAAHKRYRRLQNWVYNVLERPRGWAFVYHVFIFLLVFSCLVLSVLST
  IQEHQELANECLLILEFVMIVVFGLEYIVRVWSAGCCCRYRGWQGRFRFARKPFCVIDFI
  VFVASVAVIAAGTQGNIFATSALRSMRFLQILRMVRMDRRGGTWKLLGSVVYAHSKELIT
  AWYIGFLVLIFASFLVYLAEKDANSDFSSYADSLWWGTITLTTIGYGDKTPHTWLGRVLA
  AGFALLGISFFALPAGILGSGFALKVQEQHRQKHFEKRRMPAANLIQAAWRLYSTDMSRA
  YLTATWYYYDSILPSFRELALLFEHVQRARNGGLRPLEVRRAPVPDGAPSRYPPVATCHR
  PGSTSFCPGESSRMGIKDRIRMGSSQRRTGPSKQHLAPPTMPTSPSSEQVGEATSPTKVQ
  KSWSFNDRTRFRASLRLKPRTSAEDAPSEEVAEEKSYQCELTVDDIMPAVKTVIRSIRIL
  KFLVAKRKFKETLRPYDVKDVIEQYSAGHLDMLGRIKSLQTRVDQIVGRGPGDRKAREKG
  DKGPSDAEVVDEISMMGRVVKVEKQVQSIEHKLDLLLGFYSRCLRSGTSASLGAVQVPLF
  DPDITSDYHSPVDHEDISVSAQTLSISRSVSTNMD
• Function: Probably important in the regulation of neuronal excitability. May underlie a potassium current involved in regulating the excitability of sensory cells of the cochlea. KCNQ4 channels are blocked by linopirdin, XE991 and bepridil, whereas clofilium is without significant effect. Muscarinic agonist oxotremorine-M strongly suppress KCNQ4 current in CHO cells in which cloned KCNQ4 channels were coexpressed with M1 muscarinic receptors.
• Tissue Specificity: Expressed in the outer, but not the inner, sensory hair cells of the cochlea. Slightly expressed in heart, brain and skeletal muscle.
• KEGG Pathway: Cholinergic sy.pse (hsa04725)
• Reactome Pathway:
  Sensory processing of sound by inner hair cells of the cochlea (R-HSA-9662360)
  Sensory processing of sound by outer hair cells of the cochlea (R-HSA-9662361)
  Voltage gated Potassium channels (R-HSA-1296072)

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Nonsyndromic genetic hearing loss	DISZX61P	Definitive	Autosomal dominant	[1]
Autosomal dominant nonsyndromic hearing loss 2A	DIS81FPP	Strong	Autosomal dominant	[2]
Autosomal dominant nonsyndromic hearing loss	DISYC1G0	Supportive	Autosomal dominant	[3]

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 4 (KCNQ4).	[4]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Potassium voltage-gated channel subfamily KQT member 4 (KCNQ4).	[8]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Potassium voltage-gated channel subfamily KQT member 4 (KCNQ4).	[10]

11 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 4 (KCNQ4).	[5]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Potassium voltage-gated channel subfamily KQT member 4 (KCNQ4).	[6]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Potassium voltage-gated channel subfamily KQT member 4 (KCNQ4).	[7]
Amphotericin B	DMTAJQE	Approved	Amphotericin B decreases the expression of Potassium voltage-gated channel subfamily KQT member 4 (KCNQ4).	[6]
Cyclophosphamide	DM4O2Z7	Approved	Cyclophosphamide decreases the expression of Potassium voltage-gated channel subfamily KQT member 4 (KCNQ4).	[6]
Gentamicin	DMKINJO	Approved	Gentamicin decreases the expression of Potassium voltage-gated channel subfamily KQT member 4 (KCNQ4).	[6]
Retigabine	DMGNYIH	Approved	Retigabine increases the activity of Potassium voltage-gated channel subfamily KQT member 4 (KCNQ4).	[9]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Potassium voltage-gated channel subfamily KQT member 4 (KCNQ4).	[11]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Potassium voltage-gated channel subfamily KQT member 4 (KCNQ4).	[12]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Potassium voltage-gated channel subfamily KQT member 4 (KCNQ4).	[13]
BENZOYLENUREA	DMY5O1U	Investigative	BENZOYLENUREA increases the activity of Potassium voltage-gated channel subfamily KQT member 4 (KCNQ4).	[14]

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] Mutations in the KCNQ4 gene are responsible for autosomal dominant deafness in four DFNA2 families. Hum Mol Genet. 1999 Jul;8(7):1321-8. doi: 10.1093/hmg/8.7.1321.
• [3] Genetic Hearing Loss Overview. 1999 Feb 14 [updated 2023 Sep 28]. 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.
• [4] 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.
• [5] 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.
• [6] Effect of nephrotoxicants and hepatotoxicants on gene expression profile in human peripheral blood mononuclear cells. Biochem Biophys Res Commun. 2010 Oct 15;401(2):245-50. doi: 10.1016/j.bbrc.2010.09.039. Epub 2010 Sep 16.
• [7] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [8] 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.
• [9] The acrylamide (S)-1 differentially affects Kv7 (KCNQ) potassium channels. Neuropharmacology. 2006 Nov;51(6):1068-77.
• [10] 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.
• [11] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
• [12] 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.
• [13] 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.
• [14] 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.