Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTS315DX)

• DOT Name: Chloride intracellular channel protein 5 (CLIC5)
• Gene Name: CLIC5
• Related Disease:
  Childhood acute lymphoblastic leukemia
  Autosomal recessive nonsyndromic hearing loss 103
  Hearing loss, autosomal recessive
• UniProt ID: CLIC5_HUMAN
• PDB ID: 6Y2H
• Pfam ID: PF13410 ; PF13409
• Sequence:
  MNDEDYSTIYDTIQNERTYEVPDQPEENESPHYDDVHEYLRPENDLYATQLNTHEYDFVS
  VYTIKGEETSLASVQSEDRGYLLPDEIYSELQEAHPGEPQEDRGISMEGLYSSTQDQQLC
  AAELQENGSVMKEDLPSPSSFTIQHSKAFSTTKYSCYSDAEGLEEKEGAHMNPEIYLFVK
  AGIDGESIGNCPFSQRLFMILWLKGVVFNVTTVDLKRKPADLHNLAPGTHPPFLTFNGDV
  KTDVNKIEEFLEETLTPEKYPKLAAKHRESNTAGIDIFSKFSAYIKNTKQQNNAALERGL
  TKALKKLDDYLNTPLPEEIDANTCGEDKGSRRKFLDGDELTLADCNLLPKLHVVKIVAKK
  YRNYDIPAEMTGLWRYLKNAYARDEFTNTCAADSEIELAYADVAKRLSRS
• Function: Required for normal hearing. It is necessary for the formation of stereocilia in the inner ear and normal development of the organ of Corti. Can insert into membranes and form poorly selective ion channels that may also transport chloride ions. May play a role in the regulation of transepithelial ion absorption and secretion. Is required for the development and/or maintenance of the proper glomerular endothelial cell and podocyte architecture. Plays a role in formation of the lens suture in the eye, which is important for normal optical properties of the lens.
• Tissue Specificity: Widely expressed in both fetal and adult human tissues . Isoform 1 is expressed in renal glomeruli endothelial cells and podocytes (at protein level).
• Reactome Pathway:
  Sensory processing of sound by outer hair cells of the cochlea (R-HSA-9662361)
  Sensory processing of sound by inner hair cells of the cochlea (R-HSA-9662360)

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Childhood acute lymphoblastic leukemia	DISJ5D6U	Strong	Biomarker	[1]
Autosomal recessive nonsyndromic hearing loss 103	DISJM4HA	Moderate	Autosomal recessive	[2]
Hearing loss, autosomal recessive	DIS8G9R9	Supportive	Autosomal recessive	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Chloride intracellular channel protein 5 (CLIC5).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Chloride intracellular channel protein 5 (CLIC5).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Chloride intracellular channel protein 5 (CLIC5).	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Chloride intracellular channel protein 5 (CLIC5).	[6]
Estradiol	DMUNTE3	Approved	Estradiol affects the expression of Chloride intracellular channel protein 5 (CLIC5).	[7]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Chloride intracellular channel protein 5 (CLIC5).	[9]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Chloride intracellular channel protein 5 (CLIC5).	[10]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Chloride intracellular channel protein 5 (CLIC5).	[13]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Chloride intracellular channel protein 5 (CLIC5).	[8]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Chloride intracellular channel protein 5 (CLIC5).	[11]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Chloride intracellular channel protein 5 (CLIC5).	[12]

References

• [1] CLIC5: a novel ETV6 target gene in childhood acute lymphoblastic leukemia.Haematologica. 2016 Dec;101(12):1534-1543. doi: 10.3324/haematol.2016.149740. Epub 2016 Aug 18.
• [2] Progressive hearing loss and vestibular dysfunction caused by a homozygous nonsense mutation in CLIC5. Eur J Hum Genet. 2015 Feb;23(2):189-94. doi: 10.1038/ejhg.2014.83. Epub 2014 Apr 30.
• [3] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [4] 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.
• [5] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [6] 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.
• [7] Research resource: STR DNA profile and gene expression comparisons of human BG-1 cells and a BG-1/MCF-7 clonal variant. Mol Endocrinol. 2014 Dec;28(12):2072-81.
• [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] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [10] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [11] 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.
• [12] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [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.