Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTVD6IBL)

• DOT Name: Claudin-19 (CLDN19)
• Gene Name: CLDN19
• Related Disease:
  Chronic kidney disease
  Nephropathy
  Renal hypomagnesemia 5 with ocular involvement
  Amelogenesis imperfecta
  Diabetic retinopathy
  End-stage renal disease
  Kidney failure
  Renal hypomagnesemia 2
  Chronic renal failure
  Familial primary hypomagnesemia
  Nephrocalcinosis
  Non-insulin dependent diabetes
• UniProt ID: CLD19_HUMAN
• Pfam ID: PF00822
• Sequence:
  MANSGLQLLGYFLALGGWVGIIASTALPQWKQSSYAGDAIITAVGLYEGLWMSCASQSTG
  QVQCKLYDSLLALDGHIQSARALMVVAVLLGFVAMVLSVVGMKCTRVGDSNPIAKGRVAI
  AGGALFILAGLCTLTAVSWYATLVTQEFFNPSTPVNARYEFGPALFVGWASAGLAVLGGS
  FLCCTCPEPERPNSSPQPYRPGPSAAAREPVVKLPASAKGPLGV
• Function: Plays a major role in tight junction-specific obliteration of the intercellular space, through calcium-independent cell-adhesion activity.
• 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

12 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Chronic kidney disease	DISW82R7	Definitive	Genetic Variation	[1]
Nephropathy	DISXWP4P	Definitive	Genetic Variation	[2]
Renal hypomagnesemia 5 with ocular involvement	DISMH59P	Definitive	Mitochondrial	[3]
Amelogenesis imperfecta	DISGYR9E	Strong	Altered Expression	[4]
Diabetic retinopathy	DISHGUJM	Strong	Altered Expression	[5]
End-stage renal disease	DISXA7GG	Strong	Genetic Variation	[6]
Kidney failure	DISOVQ9P	moderate	Genetic Variation	[7]
Renal hypomagnesemia 2	DISAK1QC	moderate	Genetic Variation	[6]
Chronic renal failure	DISGG7K6	Disputed	Genetic Variation	[1]
Familial primary hypomagnesemia	DIS6TTKI	Limited	Genetic Variation	[8]
Nephrocalcinosis	DIS5ZVJP	Limited	Genetic Variation	[8]
Non-insulin dependent diabetes	DISK1O5Z	Limited	Genetic Variation	[9]

1 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 Claudin-19 (CLDN19).	[10]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Claudin-19 (CLDN19).	[11]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Claudin-19 (CLDN19).	[12]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of Claudin-19 (CLDN19).	[13]

References

• [1] Claudin-19 mutations and clinical phenotype in Spanish patients with familial hypomagnesemia with hypercalciuria and nephrocalcinosis.PLoS One. 2013;8(1):e53151. doi: 10.1371/journal.pone.0053151. Epub 2013 Jan 3.
• [2] Claudins and mineral metabolism.Curr Opin Nephrol Hypertens. 2016 Jul;25(4):308-13. doi: 10.1097/MNH.0000000000000239.
• [3] Flexible and scalable diagnostic filtering of genomic variants using G2P with Ensembl VEP. Nat Commun. 2019 May 30;10(1):2373. doi: 10.1038/s41467-019-10016-3.
• [4] Amelogenesis imperfecta in familial hypomagnesaemia and hypercalciuria with nephrocalcinosis caused by CLDN19 gene mutations.J Med Genet. 2017 Jan;54(1):26-37. doi: 10.1136/jmedgenet-2016-103956. Epub 2016 Aug 16.
• [5] Ursodeoxycholic acid ameliorates diabetic retinopathy via reducing retinal inflammation and reversing the breakdown of blood-retinal barrier.Eur J Pharmacol. 2018 Dec 5;840:20-27. doi: 10.1016/j.ejphar.2018.09.027. Epub 2018 Sep 27.
• [6] Mutations in the tight-junction gene claudin 19 (CLDN19) are associated with renal magnesium wasting, renal failure, and severe ocular involvement. Am J Hum Genet. 2006 Nov;79(5):949-57. doi: 10.1086/508617. Epub 2006 Sep 19.
• [7] Establishment of urinary exosome-like vesicles isolation protocol for FHHNC patients and evaluation of different exosomal RNA extraction methods.J Transl Med. 2018 Oct 11;16(1):278. doi: 10.1186/s12967-018-1651-z.
• [8] Characterization of two novel mutations in the claudin-16 and claudin-19 genes that cause familial hypomagnesemia with hypercalciuria and nephrocalcinosis.Gene. 2019 Mar 20;689:227-234. doi: 10.1016/j.gene.2018.12.024. Epub 2018 Dec 18.
• [9] Genetic variations in magnesium-related ion channels may affect diabetes risk among African American and Hispanic American women.J Nutr. 2015 Mar;145(3):418-24. doi: 10.3945/jn.114.203489. Epub 2015 Jan 7.
• [10] 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.
• [11] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [12] Benzo[a]pyrene-induced changes in microRNA-mRNA networks. Chem Res Toxicol. 2012 Apr 16;25(4):838-49.
• [13] Comprehensive analysis of transcriptomic changes induced by low and high doses of bisphenol A in HepG2 spheroids in vitro and rat liver in vivo. Environ Res. 2019 Jun;173:124-134. doi: 10.1016/j.envres.2019.03.035. Epub 2019 Mar 18.