Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTMIG14Q)

• DOT Name: Chloride channel protein ClC-Kb (CLCNKB)
• Synonyms: Chloride channel Kb; ClC-K2
• Gene Name: CLCNKB
• Related Disease:
  Bartter disease type 3
  Bartter disease type 4B
  Bartter syndrome type 4
  Gitelman syndrome
• UniProt ID: CLCKB_HUMAN
• Pfam ID: PF00571 ; PF00654
• Sequence:
  MEEFVGLREGSSGNPVTLQELWGPCPRIRRGIRGGLEWLKQKLFRLGEDWYFLMTLGVLM
  ALVSCAMDLAVESVVRAHQWLYREIGDSHLLRYLSWTVYPVALVSFSSGFSQSITPSSGG
  SGIPEVKTMLAGVVLEDYLDIKNFGAKVVGLSCTLACGSTLFLGKVGPFVHLSVMMAAYL
  GRVRTTTIGEPENKSKQNEMLVAAAAVGVATVFAAPFSGVLFSIEVMSSHFSVWDYWRGF
  FAATCGAFMFRLLAVFNSEQETITSLYKTSFRVDVPFDLPEIFFFVALGGLCGILGSAYL
  FCQRIFFGFIRNNRFSSKLLATSKPVYSALATLVLASITYPPSAGRFLASRLSMKQHLDS
  LFDNHSWALMTQNSSPPWPEELDPQHLWWEWYHPRFTIFGTLAFFLVMKFWMLILATTIP
  MPAGYFMPIFVYGAAIGRLFGETLSFIFPEGIVAGGITNPIMPGGYALAGAAAFSGAVTH
  TISTALLAFEVTGQIVHALPVLMAVLAANAIAQSCQPSFYDGTVIVKKLPYLPRILGRNI
  GSHRVRVEHFMNHSITTLAKDMPLEEVVKVVTSTDVAKYPLVESTESQILVGIVRRAQLV
  QALKAEPPSWAPGHQQCLQDILAAGCPTEPVTLKLSPETSLHEAHNLFELLNLHSLFVTS
  RGRAVGCVSWVEMKKAISNLTNPPAPK
• Function: Voltage-gated chloride channel. Chloride channels have several functions including the regulation of cell volume; membrane potential stabilization, signal transduction and transepithelial transport. May be important in urinary concentrating mechanisms.
• Tissue Specificity: Expressed predominantly in the kidney.
• KEGG Pathway: Collecting duct acid secretion (hsa04966)
• 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
Bartter disease type 3	DISJJPTS	Strong	Autosomal recessive	[1]
Bartter disease type 4B	DISEO5RL	Strong	Autosomal recessive	[2]
Bartter syndrome type 4	DISH9V6T	Supportive	Autosomal recessive	[2]
Gitelman syndrome	DISEM9V2	Supportive	Autosomal recessive	[3]

2 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 Chloride channel protein ClC-Kb (CLCNKB).	[4]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Chloride channel protein ClC-Kb (CLCNKB).	[7]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Zoledronate	DMIXC7G	Approved	Zoledronate decreases the expression of Chloride channel protein ClC-Kb (CLCNKB).	[5]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Chloride channel protein ClC-Kb (CLCNKB).	[6]

References

• [1] Clinical presentation of genetically defined patients with hypokalemic salt-losing tubulopathies. Am J Med. 2002 Feb 15;112(3):183-90. doi: 10.1016/s0002-9343(01)01086-5.
• [2] Molecular analysis of digenic inheritance in Bartter syndrome with sensorineural deafness. J Med Genet. 2008 Mar;45(3):182-6. doi: 10.1136/jmg.2007.052944.
• [3] Gitelman syndrome due to p.A204T mutation in CLCNKB gene. Int Urol Nephrol. 2010 Dec;42(4):1099-102. doi: 10.1007/s11255-010-9850-4. Epub 2010 Oct 8.
• [4] 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.
• [5] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [6] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [7] 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.