Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTDBURM4)

• DOT Name: Chloride intracellular channel protein 2 (CLIC2)
• Synonyms: XAP121
• Gene Name: CLIC2
• Related Disease:
  Atrial fibrillation
  Dilated cardiomyopathy 1A
  Intellectual disability
  Malignant thymoma
  Systemic lupus erythematosus
  Congestive heart failure
  X-linked intellectual disability-cardiomegaly-congestive heart failure syndrome
  X-linked complex neurodevelopmental disorder
• UniProt ID: CLIC2_HUMAN
• PDB ID: 2PER; 2R4V; 2R5G
• Pfam ID: PF13410 ; PF13409
• Sequence:
  MSGLRPGTQVDPEIELFVKAGSDGESIGNCPFCQRLFMILWLKGVKFNVTTVDMTRKPEE
  LKDLAPGTNPPFLVYNKELKTDFIKIEEFLEQTLAPPRYPHLSPKYKESFDVGCNLFAKF
  SAYIKNTQKEANKNFEKSLLKEFKRLDDYLNTPLLDEIDPDSAEEPPVSRRLFLDGDQLT
  LADCSLLPKLNIIKVAAKKYRDFDIPAEFSGVWRYLHNAYAREEFTHTCPEDKEIENTYA
  NVAKQKS
• Function: Can insert into membranes and form chloride ion channels. Channel activity depends on the pH. Membrane insertion seems to be redox-regulated and may occur only under oxydizing conditions. Modulates the activity of RYR2 and inhibits calcium influx.
• Tissue Specificity: Expressed in adult and fetal brain, heart, skeletal muscle, liver, lung, and spleen. Detected in adult stomach and testis. Expressed in fetal thymus and kidney.
• Reactome Pathway:
  Ion homeostasis (R-HSA-5578775)
  Stimuli-sensing channels (R-HSA-2672351)

Molecular Interaction Atlas (MIA) of This DOT

8 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Atrial fibrillation	DIS15W6U	Strong	Genetic Variation	[1]
Dilated cardiomyopathy 1A	DIS0RK9Z	Strong	Altered Expression	[2]
Intellectual disability	DISMBNXP	Strong	Genetic Variation	[1]
Malignant thymoma	DIS59MOU	Strong	Biomarker	[3]
Systemic lupus erythematosus	DISI1SZ7	Strong	Altered Expression	[4]
Congestive heart failure	DIS32MEA	moderate	Genetic Variation	[1]
X-linked intellectual disability-cardiomegaly-congestive heart failure syndrome	DIS9RWMB	Moderate	X-linked	[1]
X-linked complex neurodevelopmental disorder	DISI3QE9	Disputed	X-linked	[5]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Chloride intracellular channel protein 2 (CLIC2).	[6]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Chloride intracellular channel protein 2 (CLIC2).	[7]
Demecolcine	DMCZQGK	Approved	Demecolcine increases the expression of Chloride intracellular channel protein 2 (CLIC2).	[8]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Chloride intracellular channel protein 2 (CLIC2).	[10]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Chloride intracellular channel protein 2 (CLIC2).	[8]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Chloride intracellular channel protein 2 (CLIC2).	[9]

References

• [1] An X-linked channelopathy with cardiomegaly due to a CLIC2 mutation enhancing ryanodine receptor channel activity. Hum Mol Genet. 2012 Oct 15;21(20):4497-507. doi: 10.1093/hmg/dds292. Epub 2012 Jul 19.
• [2] Differential gene expression of cardiac ion channels in human dilated cardiomyopathy.PLoS One. 2013 Dec 5;8(12):e79792. doi: 10.1371/journal.pone.0079792. eCollection 2013.
• [3] Diagnosis of thymic epithelial tumor subtypes by a quantitative proteomic approach.Analyst. 2018 May 29;143(11):2491-2500. doi: 10.1039/c8an00218e.
• [4] Association of anti-CLIC2 and anti-HMGB1 autoantibodies with higher disease activity in systemic lupus erythematosus patients.J Postgrad Med. 2017 Oct-Dec;63(4):257-261. doi: 10.4103/jpgm.JPGM_499_16.
• [5] 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.
• [6] 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.
• [7] Identification of transcriptome signatures and biomarkers specific for potential developmental toxicants inhibiting human neural crest cell migration. Arch Toxicol. 2016 Jan;90(1):159-80.
• [8] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [9] 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.
• [10] Bisphenol A and bisphenol S induce distinct transcriptional profiles in differentiating human primary preadipocytes. PLoS One. 2016 Sep 29;11(9):e0163318.