Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT6YSX0G)

• DOT Name: Solute carrier family 12 member 1 (SLC12A1)
• Synonyms: Bumetanide-sensitive sodium-(potassium)-chloride cotransporter 2; Kidney-specific Na-K-Cl symporter
• Gene Name: SLC12A1
• Related Disease:
  Bartter disease type 1
  Obsolete antenatal Bartter syndrome
• UniProt ID: S12A1_HUMAN
• Pfam ID: PF00324 ; PF08403 ; PF03522
• Sequence:
  MSLNNSSNVFLDSVPSNTNRFQVSVINENHESSAAADDNTDPPHYEETSFGDEAQKRLRI
  SFRPGNQECYDNFLQSGETAKTDASFHAYDSHTNTYYLQTFGHNTMDAVPKIEYYRNTGS
  ISGPKVNRPSLLEIHEQLAKNVAVTPSSADRVANGDGIPGDEQAENKEDDQAGVVKFGWV
  KGVLVRCMLNIWGVMLFIRLSWIVGEAGIGLGVLIILLSTMVTSITGLSTSAIATNGFVR
  GGGAYYLISRSLGPEFGGSIGLIFAFANAVAVAMYVVGFAETVVDLLKESDSMMVDPTND
  IRIIGSITVVILLGISVAGMEWEAKAQVILLVILLIAIANFFIGTVIPSNNEKKSRGFFN
  YQASIFAENFGPRFTKGEGFFSVFAIFFPAATGILAGANISGDLEDPQDAIPRGTMLAIF
  ITTVAYLGVAICVGACVVRDATGNMNDTIISGMNCNGSAACGLGYDFSRCRHEPCQYGLM
  NNFQVMSMVSGFGPLITAGIFSATLSSALASLVSAPKVFQALCKDNIYKALQFFAKGYGK
  NNEPLRGYILTFLIAMAFILIAELNTIAPIISNFFLASYALINFSCFHASYAKSPGWRPA
  YGIYNMWVSLFGAVLCCAVMFVINWWAAVITYVIEFFLYVYVTCKKPDVNWGSSTQALSY
  VSALDNALELTTVEDHVKNFRPQCIVLTGGPMTRPALLDITHAFTKNSGLCICCEVFVGP
  RKLCVKEMNSGMAKKQAWLIKNKIKAFYAAVAADCFRDGVRSLLQASGLGRMKPNTLVIG
  YKKNWRKAPLTEIENYVGIIHDAFDFEIGVVIVRISQGFDISQVLQVQEELERLEQERLA
  LEATIKDNECEEESGGIRGLFKKAGKLNITKTTPKKDGSINTSQSMHVGEFNQKLVEAST
  QFKKKQEKGTIDVWWLFDDGGLTLLIPYILTLRKKWKDCKLRIYVGGKINRIEEEKIVMA
  SLLSKFRIKFADIHIIGDINIRPNKESWKVFEEMIEPYRLHESCKDLTTAEKLKRETPWK
  ITDAELEAVKEKSYRQVRLNELLQEHSRAANLIVLSLPVARKGSISDLLYMAWLEILTKN
  LPPVLLVRGNHKNVLTFYS
• Function: Renal sodium, potassium and chloride ion cotransporter that mediates the transepithelial NaCl reabsorption in the thick ascending limb and plays an essential role in the urinary concentration and volume regulation. Electrically silent transporter system.
• Tissue Specificity: Kidney; localizes to the thick ascending limbs (at protein level).
• Reactome Pathway:
  Defective SLC12A1 causes Bartter syndrome 1 (BS1) (R-HSA-5619104)
  Cation-coupled Chloride cotransporters (R-HSA-426117)

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 1	DISV9S4X	Strong	Autosomal recessive	[1]
Obsolete antenatal Bartter syndrome	DIS5WI27	Supportive	Autosomal recessive	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Solute carrier family 12 member 1 (SLC12A1).	[3]
Zoledronate	DMIXC7G	Approved	Zoledronate decreases the expression of Solute carrier family 12 member 1 (SLC12A1).	[4]
Chloroquine	DMSI5CB	Phase 3 Trial	Chloroquine decreases the expression of Solute carrier family 12 member 1 (SLC12A1).	[6]

2 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Fulvestrant	DM0YZC6	Approved	Fulvestrant decreases the methylation of Solute carrier family 12 member 1 (SLC12A1).	[5]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Solute carrier family 12 member 1 (SLC12A1).	[7]

References

• [1] Uncompensated polyuria in a mouse model of Bartter's syndrome. Proc Natl Acad Sci U S A. 2000 May 9;97(10):5434-9. doi: 10.1073/pnas.090091297.
• [2] Novel molecular variants of the Na-K-2Cl cotransporter gene are responsible for antenatal Bartter syndrome. Am J Hum Genet. 1998 Jun;62(6):1332-40. doi: 10.1086/301872.
• [3] 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.
• [4] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [5] 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.
• [6] Chronic use of chloroquine disrupts the urine concentration mechanism by lowering cAMP levels in the inner medulla. Am J Physiol Renal Physiol. 2012 Sep 15;303(6):F900-5. doi: 10.1152/ajprenal.00547.2011. Epub 2012 Jul 11.
• [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.