Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTBUHK0B)

• DOT Name: Chloride channel protein 2 (CLCN2)
• Synonyms: ClC-2
• Gene Name: CLCN2
• Related Disease:
  Leukoencephalopathy with mild cerebellar ataxia and white matter edema
  Epilepsy, idiopathic generalized, susceptibility to, 11
  Familial hyperaldosteronism type II
  Epilepsy
• UniProt ID: CLCN2_HUMAN
• PDB ID: 7XF5; 7XJA; 8GQU
• Pfam ID: PF00654
• Sequence:
  MAAAAAEEGMEPRALQYEQTLMYGRYTQDLGAFAKEEAARIRLGGPEPWKGPPSSRAAPE
  LLEYGRSRCARCRVCSVRCHKFLVSRVGEDWIFLVLLGLLMALVSWVMDYAIAACLQAQQ
  WMSRGLNTSILLQYLAWVTYPVVLITFSAGFTQILAPQAVGSGIPEMKTILRGVVLKEYL
  TLKTFIAKVIGLTCALGSGMPLGKEGPFVHIASMCAALLSKFLSLFGGIYENESRNTEML
  AAACAVGVGCCFAAPIGGVLFSIEVTSTFFAVRNYWRGFFAATFSAFIFRVLAVWNRDEE
  TITALFKTRFRLDFPFDLQELPAFAVIGIASGFGGALFVYLNRKIVQVMRKQKTINRFLM
  RKRLLFPALVTLLISTLTFPPGFGQFMAGQLSQKETLVTLFDNRTWVRQGLVEELEPPST
  SQAWNPPRANVFLTLVIFILMKFWMSALATTIPVPCGAFMPVFVIGAAFGRLVGESMAAW
  FPDGIHTDSSTYRIVPGGYAVVGAAALAGAVTHTVSTAVIVFELTGQIAHILPVMIAVIL
  ANAVAQSLQPSLYDSIIRIKKLPYLPELGWGRHQQYRVRVEDIMVRDVPHVALSCTFRDL
  RLALHRTKGRMLALVESPESMILLGSIERSQVVALLGAQLSPARRRQHMQERRATQTSPL
  SDQEGPPTPEASVCFQVNTEDSAFPAARGETHKPLKPALKRGPSVTRNLGESPTGSAESA
  GIALRSLFCGSPPPEAASEKLESCEKRKLKRVRISLASDADLEGEMSPEEILEWEEQQLD
  EPVNFSDCKIDPAPFQLVERTSLHKTHTIFSLLGVDHAYVTSIGRLIGIVTLKELRKAIE
  GSVTAQGVKVRPPLASFRDSATSSSDTETTEVHALWGPHSRHGLPREGSPSDSDDKCQ
• Function: Voltage-gated chloride channel. Chloride channels have several functions including the regulation of cell volume, membrane potential stabilization, signal transduction and transepithelial transport. Involved in the regulation of aldosterone production. The opening of CLCN2 channels at hyperpolarized membrane potentials in the glomerulosa causes cell membrane depolarization, activation of voltage-gated Ca2+ channels and increased expression of aldosterone synthase, the rate-limiting enzyme for aldosterone biosynthesis.
• Tissue Specificity: Ubiquitously expressed. Moderately expressed in aortic and coronary vascular smooth muscle cells and expressed at a low level in aortic endothelial cells. Expressed in the adrenal gland, predominantly in the zona glomerulosa .
• KEGG Pathway: Mineral absorption (hsa04978)
• Reactome Pathway: Stimuli-sensing channels (R-HSA-2672351)

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Leukoencephalopathy with mild cerebellar ataxia and white matter edema	DISZ907R	Definitive	Autosomal recessive	[1]
Epilepsy, idiopathic generalized, susceptibility to, 11	DISUIYG6	Strong	Autosomal dominant	[2]
Familial hyperaldosteronism type II	DISR8EFW	Moderate	Autosomal dominant	[3]
Epilepsy	DISBB28L	Refuted	Autosomal dominant	[4]

This DOT Affected the Regulation of Drug Effects of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Chloride	DM1TJXA	Phase 3	Chloride channel protein 2 (CLCN2) affects the transport of Chloride.	[10]

5 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 Chloride channel protein 2 (CLCN2).	[5]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Chloride channel protein 2 (CLCN2).	[6]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Chloride channel protein 2 (CLCN2).	[7]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Chloride channel protein 2 (CLCN2).	[8]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Chloride channel protein 2 (CLCN2).	[9]

References

• [1] Brain white matter oedema due to ClC-2 chloride channel deficiency: an observational analytical study. Lancet Neurol. 2013 Jul;12(7):659-68. doi: 10.1016/S1474-4422(13)70053-X. Epub 2013 May 22.
• [2] The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources. Genet Med. 2022 Aug;24(8):1732-1742. doi: 10.1016/j.gim.2022.04.017. Epub 2022 May 4.
• [3] 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.
• [4] 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.
• [5] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [6] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [7] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [8] 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.
• [9] 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.
• [10] SPI-0211 activates T84 cell chloride transport and recombinant human ClC-2 chloride currents. Am J Physiol Cell Physiol. 2004 Nov;287(5):C1173-83. doi: 10.1152/ajpcell.00528.2003. Epub 2004 Jun 22.