Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTS7GKOI)

• DOT Name: Claudin-14 (CLDN14)
• Gene Name: CLDN14
• Related Disease:
  Nonsyndromic genetic hearing loss
  Primary biliary cholangitis
  Acidosis
  Autosomal recessive nonsyndromic hearing loss 29
  Deafness
  Hepatocellular carcinoma
  Hypercalcaemia
  Hypoparathyroidism
  Neoplasm
  Perrault syndrome
  Hearing loss, autosomal recessive
  Intellectual disability
  Urolithiasis
• UniProt ID: CLD14_HUMAN
• Pfam ID: PF00822
• Sequence:
  MASTAVQLLGFLLSFLGMVGTLITTILPHWRRTAHVGTNILTAVSYLKGLWMECVWHSTG
  IYQCQIYRSLLALPQDLQAARALMVISCLLSGIACACAVIGMKCTRCAKGTPAKTTFAIL
  GGTLFILAGLLCMVAVSWTTNDVVQNFYNPLLPSGMKFEIGQALYLGFISSSLSLIGGTL
  LCLSCQDEAPYRPYQAPPRATTTTANTAPAYQPPAAYKDNRAPSVTSATHSGYRLNDYV
• Function: Plays a major role in tight junction-specific obliteration of the intercellular space, through calcium-independent cell-adhesion activity.
• Tissue Specificity: Liver, kidney. Also found in ear.
• KEGG Pathway:
  Cell adhesion molecules (hsa04514)
  Tight junction (hsa04530)
  Leukocyte transendothelial migration (hsa04670)
  Pathogenic Escherichia coli infection (hsa05130)
  Hepatitis C (hsa05160)
• Reactome Pathway: Tight junction interactions (R-HSA-420029)

Molecular Interaction Atlas (MIA) of This DOT

13 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Nonsyndromic genetic hearing loss	DISZX61P	Definitive	Autosomal recessive	[1]
Primary biliary cholangitis	DIS43E0O	Definitive	Genetic Variation	[2]
Acidosis	DISJQTX1	Strong	Biomarker	[3]
Autosomal recessive nonsyndromic hearing loss 29	DISNC0AY	Strong	Autosomal recessive	[4]
Deafness	DISKCLH4	Strong	Biomarker	[5]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[6]
Hypercalcaemia	DISKQ2K7	Strong	Biomarker	[7]
Hypoparathyroidism	DISICS0V	Strong	Biomarker	[8]
Neoplasm	DISZKGEW	Strong	Biomarker	[6]
Perrault syndrome	DISG2YOV	Strong	Genetic Variation	[9]
Hearing loss, autosomal recessive	DIS8G9R9	Supportive	Autosomal recessive	[10]
Intellectual disability	DISMBNXP	Limited	Genetic Variation	[11]
Urolithiasis	DISNFTKT	Limited	Genetic Variation	[12]

2 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 Claudin-14 (CLDN14).	[13]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Claudin-14 (CLDN14).	[24]

13 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 Claudin-14 (CLDN14).	[14]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Claudin-14 (CLDN14).	[15]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Claudin-14 (CLDN14).	[16]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Claudin-14 (CLDN14).	[17]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Claudin-14 (CLDN14).	[18]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Claudin-14 (CLDN14).	[19]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Claudin-14 (CLDN14).	[20]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Claudin-14 (CLDN14).	[21]
Ethanol	DMDRQZU	Approved	Ethanol increases the expression of Claudin-14 (CLDN14).	[22]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Claudin-14 (CLDN14).	[23]
2-AMINO-1-METHYL-6-PHENYLIMIDAZO[4,5-B]PYRIDINE	DMNQL17	Investigative	2-AMINO-1-METHYL-6-PHENYLIMIDAZO[4,5-B]PYRIDINE decreases the expression of Claudin-14 (CLDN14).	[25]
Tributylstannanyl	DMHN7CB	Investigative	Tributylstannanyl decreases the expression of Claudin-14 (CLDN14).	[26]
Methyl Mercury Ion	DM6YEW4	Investigative	Methyl Mercury Ion decreases the expression of Claudin-14 (CLDN14).	[26]

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] A Common Variant in CLDN14 is Associated with Primary Biliary Cirrhosis and Bone Mineral Density.Sci Rep. 2016 Feb 4;6:19877. doi: 10.1038/srep19877.
• [3] Chronic metabolic acidosis upregulated claudin mRNA expression in the duodenal enterocytes of female rats.Life Sci. 2007 Apr 17;80(19):1729-37. doi: 10.1016/j.lfs.2007.01.063. Epub 2007 Mar 2.
• [4] Mutations in the gene encoding tight junction claudin-14 cause autosomal recessive deafness DFNB29. Cell. 2001 Jan 12;104(1):165-72. doi: 10.1016/s0092-8674(01)00200-8.
• [5] Novel CLDN14 mutations in Pakistani families with autosomal recessive non-syndromic hearing loss.Am J Med Genet A. 2012 Feb;158A(2):315-21. doi: 10.1002/ajmg.a.34407. Epub 2012 Jan 13.
• [6] CLDN14 is epigenetically silenced by EZH2-mediated H3K27ME3 and is a novel prognostic biomarker in hepatocellular carcinoma.Carcinogenesis. 2016 Jun;37(6):557-566. doi: 10.1093/carcin/bgw036. Epub 2016 Mar 31.
• [7] Claudins and mineral metabolism.Curr Opin Nephrol Hypertens. 2016 Jul;25(4):308-13. doi: 10.1097/MNH.0000000000000239.
• [8] Parathyroid hormone controls paracellular Ca(2+) transport in the thick ascending limb by regulating the tight-junction protein Claudin14.Proc Natl Acad Sci U S A. 2017 Apr 18;114(16):E3344-E3353. doi: 10.1073/pnas.1616733114. Epub 2017 Apr 3.
• [9] Mutations of SGO2 and CLDN14 collectively cause coincidental Perrault syndrome.Clin Genet. 2017 Feb;91(2):328-332. doi: 10.1111/cge.12867. Epub 2016 Nov 16.
• [10] 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.
• [11] tSNP-based identification of allelic loss of gene expression in a patient with a balanced chromosomal rearrangement.Genomics. 2007 Apr;89(4):562-5. doi: 10.1016/j.ygeno.2006.12.006. Epub 2007 Jan 22.
• [12] Novel Risk Loci Identified in a Genome-Wide Association Study of Urolithiasis in a Japanese Population.J Am Soc Nephrol. 2019 May;30(5):855-864. doi: 10.1681/ASN.2018090942. Epub 2019 Apr 11.
• [13] 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.
• [14] 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.
• [15] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [16] 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.
• [17] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [18] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [19] Global effects of inorganic arsenic on gene expression profile in human macrophages. Mol Immunol. 2009 Feb;46(4):649-56.
• [20] Minimal peroxide exposure of neuronal cells induces multifaceted adaptive responses. PLoS One. 2010 Dec 17;5(12):e14352. doi: 10.1371/journal.pone.0014352.
• [21] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [22] Use of transcriptomics in hazard identification and next generation risk assessment: A case study with clothianidin. Food Chem Toxicol. 2022 Aug;166:113212. doi: 10.1016/j.fct.2022.113212. Epub 2022 Jun 8.
• [23] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [24] 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.
• [25] Preferential induction of the AhR gene battery in HepaRG cells after a single or repeated exposure to heterocyclic aromatic amines. Toxicol Appl Pharmacol. 2010 Nov 15;249(1):91-100.
• [26] Inhibition of CXCL12-mediated chemotaxis of Jurkat cells by direct immunotoxicants. Arch Toxicol. 2016 Jul;90(7):1685-94. doi: 10.1007/s00204-015-1585-7. Epub 2015 Aug 28.