Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT7Q0RI9)

• DOT Name: Chloride channel protein ClC-Ka (CLCNKA)
• Synonyms: Chloride channel Ka; ClC-K1
• Gene Name: CLCNKA
• Related Disease:
  Bartter disease type 4B
  Bartter syndrome type 4
• UniProt ID: CLCKA_HUMAN
• PDB ID: 2PFI
• Pfam ID: PF00571 ; PF00654
• Sequence:
  MEELVGLREGFSGDPVTLQELWGPCPHIRRAIQGGLEWLKQKVFRLGEDWYFLMTLGVLM
  ALVSYAMNFAIGCVVRAHQWLYREIGDSHLLRYLSWTVYPVALVSFSSGFSQSITPSSGG
  SGIPELKTMLAGVILEDYLDIKNFGAKVVGLSCTLATGSTLFLGKVGPFVHLSVMIAAYL
  GRVRTTTIGEPENKSKQNEMLVAAAAVGVATVFAAPFSGVLFSIEVMSSHFSVRDYWRGF
  FAATCGAFIFRLLAVFNSEQETITSLYKTSFRVDVPFDLPEIFFFVALGGICGVLSCAYL
  FCQRTFLSFIKTNRYSSKLLATSKPVYSALATLLLASITYPPGVGHFLASRLSMKQHLDS
  LFDNHSWALMTQNSSPPWPEELDPQHLWWEWYHPRFTIFGTLAFFLVMKFWMLILATTIP
  MPAGYFMPIFILGAAIGRLLGEALAVAFPEGIVTGGVTNPIMPGGYALAGAAAFSGAVTH
  TISTALLAFELTGQIVHALPVLMAVLAANAIAQSCQPSFYDGTIIVKKLPYLPRILGRNI
  GSHHVRVEHFMNHSITTLAKDTPLEEVVKVVTSTDVTEYPLVESTESQILVGIVQRAQLV
  QALQAEPPSRAPGHQQCLQDILARGCPTEPVTLTLFSETTLHQAQNLFKLLNLQSLFVTS
  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. All nephron segments expressing BSND also express CLCNK proteins.
• Reactome Pathway: Stimuli-sensing channels (R-HSA-2672351)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Bartter disease type 4B	DISEO5RL	Moderate	Unknown	[1]
Bartter syndrome type 4	DISH9V6T	Supportive	Autosomal recessive	[2]

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-Ka (CLCNKA).	[3]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Chloride channel protein ClC-Ka (CLCNKA).	[7]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Chloride channel protein ClC-Ka (CLCNKA).	[4]
Cisplatin	DMRHGI9	Approved	Cisplatin affects the expression of Chloride channel protein ClC-Ka (CLCNKA).	[5]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of Chloride channel protein ClC-Ka (CLCNKA).	[5]
Zoledronate	DMIXC7G	Approved	Zoledronate decreases the expression of Chloride channel protein ClC-Ka (CLCNKA).	[6]
Tamibarotene	DM3G74J	Phase 3	Tamibarotene decreases the expression of Chloride channel protein ClC-Ka (CLCNKA).	[4]

References

• [1] 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.
• [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] 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.
• [4] Differential modulation of PI3-kinase/Akt pathway during all-trans retinoic acid- and Am80-induced HL-60 cell differentiation revealed by DNA microarray analysis. Biochem Pharmacol. 2004 Dec 1;68(11):2177-86.
• [5] Acute hypersensitivity of pluripotent testicular cancer-derived embryonal carcinoma to low-dose 5-aza deoxycytidine is associated with global DNA Damage-associated p53 activation, anti-pluripotency and DNA demethylation. PLoS One. 2012;7(12):e53003. doi: 10.1371/journal.pone.0053003. Epub 2012 Dec 27.
• [6] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [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.