Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTHP6Y7F)

• DOT Name: Uromodulin
• Synonyms: Tamm-Horsfall urinary glycoprotein; THP
• Gene Name: UMOD
• Related Disease:
  Autosomal dominant medullary cystic kidney disease with or without hyperuricemia
  Obsolete glomerulocystic kidney disease with hyperuricemia and isosthenuria
  Familial juvenile hyperuricemic nephropathy type 1
  Obsolete autosomal dominant medullary cystic kidney disease with hyperuricemia
• UniProt ID: UROM_HUMAN
• PDB ID: 4WRN; 6TQK; 6TQL; 6ZS5; 6ZYA; 7PFP; 7Q3N
• Pfam ID: PF12947 ; PF07645 ; PF00100
• Sequence:
  MGQPSLTWMLMVVVASWFITTAATDTSEARWCSECHSNATCTEDEAVTTCTCQEGFTGDG
  LTCVDLDECAIPGAHNCSANSSCVNTPGSFSCVCPEGFRLSPGLGCTDVDECAEPGLSHC
  HALATCVNVVGSYLCVCPAGYRGDGWHCECSPGSCGPGLDCVPEGDALVCADPCQAHRTL
  DEYWRSTEYGEGYACDTDLRGWYRFVGQGGARMAETCVPVLRCNTAAPMWLNGTHPSSDE
  GIVSRKACAHWSGHCCLWDASVQVKACAGGYYVYNLTAPPECHLAYCTDPSSVEGTCEEC
  SIDEDCKSNNGRWHCQCKQDFNITDISLLEHRLECGANDMKVSLGKCQLKSLGFDKVFMY
  LSDSRCSGFNDRDNRDWVSVVTPARDGPCGTVLTRNETHATYSNTLYLADEIIIRDLNIK
  INFACSYPLDMKVSLKTALQPMVSALNIRVGGTGMFTVRMALFQTPSYTQPYQGSSVTLS
  TEAFLYVGTMLDGGDLSRFALLMTNCYATPSSNATDPLKYFIIQDRCPHTRDSTIQVVEN
  GESSQGRFSVQMFRFAGNYDLVYLHCEVYLCDTMNEKCKPTCSGTRFRSGSVIDQSRVLN
  LGPITRKGVQATVSRAFSSLGLLKVWLPLLLSATLTLTFQ
• Function: [Uromodulin]: Functions in biogenesis and organization of the apical membrane of epithelial cells of the thick ascending limb of Henle's loop (TALH), where it promotes formation of complex filamentous gel-like structure that may play a role in the water barrier permeability (Probable). May serve as a receptor for binding and endocytosis of cytokines (IL-1, IL-2) and TNF. Facilitates neutrophil migration across renal epithelia ; [Uromodulin, secreted form]: In the urine, may contribute to colloid osmotic pressure, retards passage of positively charged electrolytes, and inhibits formation of liquid containing supersaturated salts and subsequent formation of salt crystals. Protects against urinary tract infections by binding to type 1 fimbriated E.coli. Binds to bacterial adhesin fimH which mediates the stable formation of bacterial aggregates, prevents the binding of E.coli to uroplakins UPK1A and UPK1B which act as urothelial receptors for type I fimbriae, and allows for pathogen clearance through micturation. Also promotes aggregation of other bacteria including K.pneumoniae, P.aeruginosa and S.mitis and so may also protect against other uropathogens.
• Tissue Specificity: Expressed in the tubular cells of the kidney. Most abundant protein in normal urine (at protein level). Synthesized exclusively in the kidney. Expressed exclusively by epithelial cells of the thick ascending limb of Henle's loop (TALH) and of distal convoluted tubule lumen.
• Reactome Pathway: Asparagine N-linked glycosylation (R-HSA-446203)

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Autosomal dominant medullary cystic kidney disease with or without hyperuricemia	DIS3PLLZ	Definitive	Autosomal dominant	[1]
Obsolete glomerulocystic kidney disease with hyperuricemia and isosthenuria	DIS6S210	Definitive	Autosomal dominant	[2]
Familial juvenile hyperuricemic nephropathy type 1	DIS495AH	Strong	Autosomal dominant	[3]
Obsolete autosomal dominant medullary cystic kidney disease with hyperuricemia	DISB28ZB	Supportive	Autosomal dominant	[4]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Cangrelor	DM8JRH0	Approved	Uromodulin increases the Renal failure acute ADR of Cangrelor.	[7]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetazolamide	DM1AF5U	Approved	Acetazolamide increases the expression of Uromodulin.	[5]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Uromodulin.	[6]

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] 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] UROMODULIN mutations cause familial juvenile hyperuricemic nephropathy. J Clin Endocrinol Metab. 2003 Mar;88(3):1398-401. doi: 10.1210/jc.2002-021973.
• [4] Autosomal Dominant Tubulointerstitial Kidney Disease C UMOD. 2007 Jan 12 [updated 2021 Dec 23]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews(?) [Internet]. Seattle (WA): University of Washington, Seattle; 1993C2024.
• [5] Tamm-Horsfall protein accumulation in glomeruli during acetazolamide-induced acute renal failure. Am J Nephrol. 1989;9(1):56-7. doi: 10.1159/000167936.
• [6] 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.
• [7] ADReCS-Target: target profiles for aiding drug safety research and application. Nucleic Acids Res. 2018 Jan 4;46(D1):D911-D917. doi: 10.1093/nar/gkx899.