Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTJVSUK1)

• DOT Name: H(+)/Cl(-) exchange transporter 7 (CLCN7)
• Synonyms: Chloride channel 7 alpha subunit; Chloride channel protein 7; ClC-7
• Gene Name: CLCN7
• Related Disease:
  Autosomal dominant osteopetrosis 2
  Autosomal recessive osteopetrosis 4
  Hypopigmentation, organomegaly, and delayed myelination and development
  Autosomal recessive osteopetrosis 6
  Infantile malignant osteopetrosis
• UniProt ID: CLCN7_HUMAN
• PDB ID: 7BXU; 7CQ5; 7CQ6; 7CQ7; 7JM7
• Pfam ID: PF00571 ; PF00654
• Sequence:
  MANVSKKVSWSGRDRDDEEAAPLLRRTARPGGGTPLLNGAGPGAARQSPRSALFRVGHMS
  SVELDDELLDPDMDPPHPFPKEIPHNEKLLSLKYESLDYDNSENQLFLEEERRINHTAFR
  TVEIKRWVICALIGILTGLVACFIDIVVENLAGLKYRVIKGNIDKFTEKGGLSFSLLLWA
  TLNAAFVLVGSVIVAFIEPVAAGSGIPQIKCFLNGVKIPHVVRLKTLVIKVSGVILSVVG
  GLAVGKEGPMIHSGSVIAAGISQGRSTSLKRDFKIFEYFRRDTEKRDFVSAGAAAGVSAA
  FGAPVGGVLFSLEEGASFWNQFLTWRIFFASMISTFTLNFVLSIYHGNMWDLSSPGLINF
  GRFDSEKMAYTIHEIPVFIAMGVVGGVLGAVFNALNYWLTMFRIRYIHRPCLQVIEAVLV
  AAVTATVAFVLIYSSRDCQPLQGGSMSYPLQLFCADGEYNSMAAAFFNTPEKSVVSLFHD
  PPGSYNPLTLGLFTLVYFFLACWTYGLTVSAGVFIPSLLIGAAWGRLFGISLSYLTGAAI
  WADPGKYALMGAAAQLGGIVRMTLSLTVIMMEATSNVTYGFPIMLVLMTAKIVGDVFIEG
  LYDMHIQLQSVPFLHWEAPVTSHSLTAREVMSTPVTCLRRREKVGVIVDVLSDTASNHNG
  FPVVEHADDTQPARLQGLILRSQLIVLLKHKVFVERSNLGLVQRRLRLKDFRDAYPRFPP
  IQSIHVSQDERECTMDLSEFMNPSPYTVPQEASLPRVFKLFRALGLRHLVVVDNRNQVVG
  LVTRKDLARYRLGKRGLEELSLAQT
• Function: Slowly voltage-gated channel mediating the exchange of chloride ions against protons. Functions as antiporter and contributes to the acidification of the lysosome lumen and may be involved in maintaining lysosomal pH. 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: Brain and kidney.
• Reactome Pathway: Stimuli-sensing channels (R-HSA-2672351)

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Autosomal dominant osteopetrosis 2	DISC8H8S	Definitive	Autosomal dominant	[1]
Autosomal recessive osteopetrosis 4	DISI71VA	Definitive	Autosomal recessive	[1]
Hypopigmentation, organomegaly, and delayed myelination and development	DISKEF9P	Strong	Autosomal dominant	[2]
Autosomal recessive osteopetrosis 6	DIS5LWCT	Supportive	Autosomal recessive	[3]
Infantile malignant osteopetrosis	DIS8C3LZ	Supportive	Autosomal recessive	[4]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Apilimod dimesylate	DM4N2O0	Phase 2	H(+)/Cl(-) exchange transporter 7 (CLCN7) affects the response to substance of Apilimod dimesylate.	[12]

4 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 H(+)/Cl(-) exchange transporter 7 (CLCN7).	[5]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of H(+)/Cl(-) exchange transporter 7 (CLCN7).	[8]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of H(+)/Cl(-) exchange transporter 7 (CLCN7).	[10]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of H(+)/Cl(-) exchange transporter 7 (CLCN7).	[11]

3 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 H(+)/Cl(-) exchange transporter 7 (CLCN7).	[6]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of H(+)/Cl(-) exchange transporter 7 (CLCN7).	[7]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of H(+)/Cl(-) exchange transporter 7 (CLCN7).	[9]

References

• [1] 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.
• [2] Lysosomal Storage and Albinism Due to Effects of a De Novo CLCN7 Variant on Lysosomal Acidification. Am J Hum Genet. 2019 Jun 6;104(6):1127-1138. doi: 10.1016/j.ajhg.2019.04.008. Epub 2019 May 30.
• [3] Chloride channel 7 (CLCN7) gene mutations in intermediate autosomal recessive osteopetrosis. Hum Genet. 2003 Feb;112(2):186-9. doi: 10.1007/s00439-002-0861-9. Epub 2002 Nov 7.
• [4] Long-term survival in infantile malignant autosomal recessive osteopetrosis secondary to homozygous p.Arg526Gln mutation in CLCN7. Am J Med Genet A. 2012 Apr;158A(4):909-16. doi: 10.1002/ajmg.a.35264. Epub 2012 Mar 14.
• [5] 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.
• [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] 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.
• [8] 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.
• [9] 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.
• [10] 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.
• [11] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [12] Identification of apilimod as a first-in-class PIKfyve kinase inhibitor for treatment of B-cell non-Hodgkin lymphoma. Blood. 2017 Mar 30;129(13):1768-1778. doi: 10.1182/blood-2016-09-736892. Epub 2017 Jan 19.