Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT4A2UWF)

• DOT Name: H(+)/Cl(-) exchange transporter 4 (CLCN4)
• Synonyms: Chloride channel protein 4; ClC-4; Chloride transporter ClC-4
• Gene Name: CLCN4
• Related Disease:
  Classic lissencephaly
  Non-syndromic X-linked intellectual disability
  X-linked intellectual disability
  Chondrodysplasia punctata
  Colon cancer
  Colon carcinoma
  Dent disease
  Epilepsy
  Glioma
  Intellectual disability, X-linked 1
  Intellectual disability, X-linked 49
  Linear skin defects with multiple congenital anomalies 1
  Metastatic malignant neoplasm
  Neuroblastoma
  X-linked recessive ocular albinism
  Intellectual disability
• UniProt ID: CLCN4_HUMAN
• Pfam ID: PF00571 ; PF00654
• Sequence:
  MVNAGAMSGSGNLMDFLDEPFPDVGTYEDFHTIDWLREKSRDTDRHRKITSKSKESIWEF
  IKSLLDAWSGWVVMLLIGLLAGTLAGVIDLAVDWMTDLKEGVCLSAFWYSHEQCCWTSNE
  TTFEDRDKCPLWQKWSELLVNQSEGASAYILNYLMYILWALLFAFLAVSLVRVFAPYACG
  SGIPEIKTILSGFIIRGYLGKWTLLIKTVTLVLVVSSGLSLGKEGPLVHVACCCGNFFSS
  LFSKYSKNEGKRREVLSAAAAAGVSVAFGAPIGGVLFSLEEVSYYFPLKTLWRSFFAALV
  AAFTLRSINPFGNSRLVLFYVEYHTPWYMAELFPFILLGVFGGLWGTLFIRCNIAWCRRR
  KTTRLGKYPVLEVIVVTAITAIIAYPNPYTRQSTSELISELFNDCGALESSQLCDYINDP
  NMTRPVDDIPDRPAGVGVYTAMWQLALALIFKIVVTIFTFGMKIPSGLFIPSMAVGAIAG
  RMVGIGVEQLAYHHHDWIIFRNWCRPGADCVTPGLYAMVGAAACLGGVTRMTVSLVVIMF
  ELTGGLEYIVPLMAAAVTSKWVADAFGKEGIYEAHIHLNGYPFLDVKDEFTHRTLATDVM
  RPRRGEPPLSVLTQDSMTVEDVETLIKETDYNGFPVVVSRDSERLIGFAQRRELILAIKN
  ARQRQEGIVSNSIMYFTEEPPELPANSPHPLKLRRILNLSPFTVTDHTPMETVVDIFRKL
  GLRQCLVTRSGRLLGIITKKDVLRHMAQMANQDPESIMFN
• Function: Strongly outwardly rectifying, electrogenic H(+)/Cl(-)exchanger which mediates the exchange of chloride ions against protons. The CLC channel family contains both chloride channels and proton-coupled anion transporters that exchange chloride or another anion for protons. The presence of conserved gating glutamate residues is typical for family members that function as antiporters.
• Tissue Specificity: Abundant in skeletal muscle and also detectable in brain and heart.
• KEGG Pathway: Neutrophil extracellular trap formation (hsa04613)
• Reactome Pathway: Stimuli-sensing channels (R-HSA-2672351)

Molecular Interaction Atlas (MIA) of This DOT

16 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Classic lissencephaly	DISR8S3S	Definitive	Biomarker	[1]
Non-syndromic X-linked intellectual disability	DIS71AI3	Definitive	X-linked	[2]
X-linked intellectual disability	DISYJBY3	Definitive	Genetic Variation	[3]
Chondrodysplasia punctata	DISERVGO	Strong	Genetic Variation	[4]
Colon cancer	DISVC52G	Strong	Biomarker	[5]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[5]
Dent disease	DISRDLFN	Strong	Genetic Variation	[6]
Epilepsy	DISBB28L	Strong	Genetic Variation	[7]
Glioma	DIS5RPEH	Strong	Altered Expression	[8]
Intellectual disability, X-linked 1	DISET38E	Strong	GermlineCausalMutation	[9]
Intellectual disability, X-linked 49	DISKDVXD	Strong	X-linked	[10]
Linear skin defects with multiple congenital anomalies 1	DISNYKBT	Strong	Genetic Variation	[11]
Metastatic malignant neoplasm	DIS86UK6	Strong	Biomarker	[5]
Neuroblastoma	DISVZBI4	Strong	Altered Expression	[8]
X-linked recessive ocular albinism	DISI9S32	Strong	Biomarker	[12]
Intellectual disability	DISMBNXP	Disputed	Genetic Variation	[7]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of H(+)/Cl(-) exchange transporter 4 (CLCN4).	[13]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of H(+)/Cl(-) exchange transporter 4 (CLCN4).	[14]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of H(+)/Cl(-) exchange transporter 4 (CLCN4).	[15]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of H(+)/Cl(-) exchange transporter 4 (CLCN4).	[16]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of H(+)/Cl(-) exchange transporter 4 (CLCN4).	[17]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of H(+)/Cl(-) exchange transporter 4 (CLCN4).	[19]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of H(+)/Cl(-) exchange transporter 4 (CLCN4).	[20]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of H(+)/Cl(-) exchange transporter 4 (CLCN4).	[21]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of H(+)/Cl(-) exchange transporter 4 (CLCN4).	[22]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane increases the expression of H(+)/Cl(-) exchange transporter 4 (CLCN4).	[23]

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 affects the methylation of H(+)/Cl(-) exchange transporter 4 (CLCN4).	[18]

References

• [1] Gene Profiling of Nucleus Basalis Tau Containing Neurons in Chronic Traumatic Encephalopathy: A Chronic Effects of Neurotrauma Consortium Study.J Neurotrauma. 2018 Jun 1;35(11):1260-1271. doi: 10.1089/neu.2017.5368. Epub 2018 Apr 5.
• [2] 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.
• [3] X-linked mental retardation with neonatal hypotonia in a French family (MRX15): gene assignment to Xp11.22-Xp21.1.Am J Med Genet. 1996 Jul 12;64(1):97-106. doi: 10.1002/(SICI)1096-8628(19960712)64:1<97::AID-AJMG17>3.0.CO;2-N.
• [4] Lri-Weill syndrome as part of a contiguous gene syndrome at Xp22.3.Am J Med Genet. 1999 Apr 23;83(5):367-71. doi: 10.1002/(sici)1096-8628(19990423)83:5<367::aid-ajmg5>3.0.co;2-k.
• [5] Gene trapping identifies chloride channel 4 as a novel inducer of colon cancer cell migration, invasion and metastases.Br J Cancer. 2010 Feb 16;102(4):774-82. doi: 10.1038/sj.bjc.6605536. Epub 2010 Jan 19.
• [6] Mutational analysis of CLC-5, cofilin and CLC-4 in patients with Dent's disease.Nephron Physiol. 2009;112(4):p53-62. doi: 10.1159/000225944. Epub 2009 Jun 20.
• [7] De novo and inherited mutations in the X-linked gene CLCN4 are associated with syndromic intellectual disability and behavior and seizure disorders in males and females.Mol Psychiatry. 2018 Feb;23(2):222-230. doi: 10.1038/mp.2016.135. Epub 2016 Aug 23.
• [8] Clozapine induces chloride channel-4 expression through PKA activation and modulates CDK5 expression in SH-SY5Y and U87 cells.Prog Neuropsychopharmacol Biol Psychiatry. 2015 Jan 2;56:168-73. doi: 10.1016/j.pnpbp.2014.09.002. Epub 2014 Sep 20.
• [9] X-exome sequencing of 405 unresolved families identifies seven novel intellectual disability genes. Mol Psychiatry. 2016 Jan;21(1):133-48. doi: 10.1038/mp.2014.193. Epub 2015 Feb 3.
• [10] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [11] Intragenic TaqI restriction fragment length polymorphism (RFLP) in CICN4, between the loci for X-linked ocular albinism (OA1) and microphthalmia with linear skin defects syndrome (MLS).Hum Genet. 1995 May;95(5):594-5. doi: 10.1007/BF00223880.
• [12] A new region of conservation is defined between human and mouse X chromosomes.Genomics. 1996 Jul 1;35(1):244-7. doi: 10.1006/geno.1996.0347.
• [13] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [14] 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.
• [15] 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.
• [16] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [17] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [18] 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.
• [19] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [20] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [21] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [22] 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.
• [23] Transcriptome and DNA methylation changes modulated by sulforaphane induce cell cycle arrest, apoptosis, DNA damage, and suppression of proliferation in human liver cancer cells. Food Chem Toxicol. 2020 Feb;136:111047. doi: 10.1016/j.fct.2019.111047. Epub 2019 Dec 12.