Details of Drug Off-Target (DOT)

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

• DOT Name: Claudin-16 (CLDN16)
• Synonyms: Paracellin-1; PCLN-1
• Gene Name: CLDN16
• Related Disease:
  Advanced cancer
  Amelogenesis imperfecta
  Amyloidosis
  Breast cancer
  Breast carcinoma
  Chronic renal failure
  End-stage renal disease
  Kidney failure
  Lung cancer
  Lung carcinoma
  Neoplasm
  Nephropathy
  Renal hypomagnesemia 2
  Renal hypomagnesemia 3
  Rickets
  Chronic kidney disease
  Dent disease
  Intestinal hypomagnesemia 1
  High blood pressure
  Thyroid gland papillary carcinoma
• UniProt ID: CLD16_HUMAN
• Pfam ID: PF00822
• Sequence:
  MRDLLQYIACFFAFFSAGFLIVATWTDCWMVNADDSLEVSTKCRGLWWECVTNAFDGIRT
  CDEYDSILAEHPLKLVVTRALMITADILAGFGFLTLLLGLDCVKFLPDEPYIKVRICFVA
  GATLLIAGTPGIIGSVWYAVDVYVERSTLVLHNIFLGIQYKFGWSCWLGMAGSLGCFLAG
  AVLTCCLYLFKDVGPERNYPYSLRKAYSAAGVSMAKSYSAPRTETAKMYAVDTRV
• Function: Plays a major role in tight junction-specific obliteration of the intercellular space, through calcium-independent cell-adhesion activity. Involved in paracellular magnesium reabsorption. Required for a selective paracellular conductance. May form, alone or in partnership with other constituents, an intercellular pore permitting paracellular passage of magnesium and calcium ions down their electrochemical gradients. Alternatively, it could be a sensor of magnesium concentration that could alter paracellular permeability mediated by other factors.
• Tissue Specificity: Kidney-specific, including the thick ascending limb of Henle (TAL).
• 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

20 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[1]
Amelogenesis imperfecta	DISGYR9E	Strong	Genetic Variation	[2]
Amyloidosis	DISHTAI2	Strong	Biomarker	[3]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[1]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[1]
Chronic renal failure	DISGG7K6	Strong	Genetic Variation	[4]
End-stage renal disease	DISXA7GG	Strong	Genetic Variation	[4]
Kidney failure	DISOVQ9P	Strong	Genetic Variation	[5]
Lung cancer	DISCM4YA	Strong	Genetic Variation	[6]
Lung carcinoma	DISTR26C	Strong	Genetic Variation	[6]
Neoplasm	DISZKGEW	Strong	Altered Expression	[1]
Nephropathy	DISXWP4P	Strong	Biomarker	[7]
Renal hypomagnesemia 2	DISAK1QC	Strong	Biomarker	[8]
Renal hypomagnesemia 3	DIS9K58C	Strong	Autosomal recessive	[9]
Rickets	DISH89YF	Strong	Genetic Variation	[10]
Chronic kidney disease	DISW82R7	moderate	Genetic Variation	[11]
Dent disease	DISRDLFN	moderate	Biomarker	[12]
Intestinal hypomagnesemia 1	DISKMKFJ	moderate	Genetic Variation	[13]
High blood pressure	DISY2OHH	Disputed	Biomarker	[14]
Thyroid gland papillary carcinoma	DIS48YMM	Limited	Altered Expression	[15]

8 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-16 (CLDN16).	[16]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Claudin-16 (CLDN16).	[17]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Claudin-16 (CLDN16).	[18]
Zoledronate	DMIXC7G	Approved	Zoledronate decreases the expression of Claudin-16 (CLDN16).	[19]
Ethanol	DMDRQZU	Approved	Ethanol increases the expression of Claudin-16 (CLDN16).	[20]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of Claudin-16 (CLDN16).	[18]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Claudin-16 (CLDN16).	[21]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of Claudin-16 (CLDN16).	[22]

References

• [1] Claudin-16/paracellin-1, cloning, expression, and its role in tight junction functions in cancer and endothelial cells.Methods Mol Biol. 2011;762:383-407. doi: 10.1007/978-1-61779-185-7_28.
• [2] Claudin-16 Deficiency Impairs Tight Junction Function in Ameloblasts, Leading to Abnormal Enamel Formation.J Bone Miner Res. 2016 Mar;31(3):498-513. doi: 10.1002/jbmr.2726. Epub 2015 Oct 20.
• [3] Sex-specific genetic predictors of Alzheimer's disease biomarkers.Acta Neuropathol. 2018 Dec;136(6):857-872. doi: 10.1007/s00401-018-1881-4. Epub 2018 Jul 2.
• [4] Follow-up of five patients with FHHNC due to mutations in the Paracellin-1 gene.Pediatr Nephrol. 2002 Aug;17(8):602-8. doi: 10.1007/s00467-002-0884-4. Epub 2002 Jun 11.
• [5] Familial hypomagnesemia with hypercalciuria and nephrocalcinosis: blocking endocytosis restores surface expression of a novel Claudin-16 mutant that lacks the entire C-terminal cytosolic tail.Hum Mol Genet. 2006 Apr 1;15(7):1049-58. doi: 10.1093/hmg/ddl020. Epub 2006 Feb 24.
• [6] Genome-wide analysis of expression quantitative trait loci identified potential lung cancer susceptibility variants among Asian populations.Carcinogenesis. 2019 Apr 29;40(2):263-268. doi: 10.1093/carcin/bgy165.
• [7] Down-regulation of magnesium transporting molecule, claudin-16, as a possible cause of hypermagnesiuria with the development of tubulo-interstitial nephropathy.Magnes Res. 2018 Feb 1;31(1):11-23. doi: 10.1684/mrh.2018.0434.
• [8] Disorders of renal magnesium handling explain renal magnesium transport.J Nephrol. 2007 Sep-Oct;20(5):507-10.
• [9] Paracellin-1, a renal tight junction protein required for paracellular Mg2+ resorption. Science. 1999 Jul 2;285(5424):103-6. doi: 10.1126/science.285.5424.103.
• [10] Genetic causes of hypercalciuric nephrolithiasis.Pediatr Nephrol. 2009 Dec;24(12):2321-32. doi: 10.1007/s00467-008-0807-0. Epub 2008 Apr 30.
• [11] Identification of the first large deletion in the CLDN16 gene in a patient with FHHNC and late-onset of chronic kidney disease: case report.BMC Nephrol. 2015 Jul 2;16:92. doi: 10.1186/s12882-015-0079-4.
• [12] Inherited hypercalciuric syndromes: Dent's disease (CLC-5) and familial hypomagnesemia with hypercalciuria (paracellin-1).Semin Nephrol. 2004 Jan;24(1):55-60. doi: 10.1053/j.semnephrol.2003.08.011.
• [13] Clinical and molecular characterization of Turkish patients with familial hypomagnesaemia: novel mutations in TRPM6 and CLDN16 genes.Nephrol Dial Transplant. 2012 Feb;27(2):667-73. doi: 10.1093/ndt/gfr300. Epub 2011 Jun 9.
• [14] Dysfunction of paracellin-1 by dephosphorylation in Dahl salt-sensitive hypertensive rats.J Physiol Sci. 2006 Oct;56(5):379-83. doi: 10.2170/physiolsci.SC008906. Epub 2006 Sep 9.
• [15] Gene expression in poorly differentiated papillary thyroid carcinomas.Thyroid. 2006 Feb;16(2):161-75. doi: 10.1089/thy.2006.16.161.
• [16] Evidence for a role of claudin 2 as a proximal tubular stress responsive paracellular water channel. Toxicol Appl Pharmacol. 2014 Sep 1;279(2):163-72.
• [17] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [18] Genistein and bisphenol A exposure cause estrogen receptor 1 to bind thousands of sites in a cell type-specific manner. Genome Res. 2012 Nov;22(11):2153-62.
• [19] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [20] Chronic ethanol exposure increases goosecoid (GSC) expression in human embryonic carcinoma cell differentiation. J Appl Toxicol. 2014 Jan;34(1):66-75.
• [21] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [22] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.