Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTYF2UYI)

• DOT Name: Wolframin
• Gene Name: WFS1
• Related Disease:
  Wolfram syndrome
  Wolfram syndrome 1
  Wolfram-like syndrome
  Autosomal dominant nonsyndromic hearing loss 6
  Cataract 41
  Autosomal dominant nonsyndromic hearing loss
  Early-onset nuclear cataract
  Non-insulin dependent diabetes
• UniProt ID: WFS1_HUMAN
• Pfam ID: PF20053 ; PF19913 ; PF19914 ; PF20023
• Sequence:
  MDSNTAPLGPSCPQPPPAPQPQARSRLNATASLEQERSERPRAPGPQAGPGPGVRDAAAP
  AEPQAQHTRSRERADGTGPTKGDMEIPFEEVLERAKAGDPKAQTEVGKHYLQLAGDTDEE
  LNSCTAVDWLVLAAKQGRREAVKLLRRCLADRRGITSENEREVRQLSSETDLERAVRKAA
  LVMYWKLNPKKKKQVAVAELLENVGQVNEHDGGAQPGPVPKSLQKQRRMLERLVSSESKN
  YIALDDFVEITKKYAKGVIPSSLFLQDDEDDDELAGKSPEDLPLRLKVVKYPLHAIMEIK
  EYLIDMASRAGMHWLSTIIPTHHINALIFFFIVSNLTIDFFAFFIPLVIFYLSFISMVIC
  TLKVFQDSKAWENFRTLTDLLLRFEPNLDVEQAEVNFGWNHLEPYAHFLLSVFFVIFSFP
  IASKDCIPCSELAVITGFFTVTSYLSLSTHAEPYTRRALATEVTAGLLSLLPSMPLNWPY
  LKVLGQTFITVPVGHLVVLNVSVPCLLYVYLLYLFFRMAQLRNFKGTYCYLVPYLVCFMW
  CELSVVILLESTGLGLLRASIGYFLFLFALPILVAGLALVGVLQFARWFTSLELTKIAVT
  VAVCSVPLLLRWWTKASFSVVGMVKSLTRSSMVKLILVWLTAIVLFCWFYVYRSEGMKVY
  NSTLTWQQYGALCGPRAWKETNMARTQILCSHLEGHRVTWTGRFKYVRVTDIDNSAESAI
  NMLPFFIGDWMRCLYGEAYPACSPGNTSTAEEELCRLKLLAKHPCHIKKFDRYKFEITVG
  MPFSSGADGSRSREEDDVTKDIVLRASSEFKSVLLSLRQGSLIEFSTILEGRLGSKWPVF
  ELKAISCLNCMAQLSPTRRHVKIEHDWRSTVHGAVKFAFDFFFFPFLSAA
• Function: Participates in the regulation of cellular Ca(2+) homeostasis, at least partly, by modulating the filling state of the endoplasmic reticulum Ca(2+) store. Negatively regulates the ER stress response and positively regulates the stability of V-ATPase subunits ATP6V1A and ATP1B1 by preventing their degradation through an unknown proteasome-independent mechanism.
• Tissue Specificity: Highly expressed in heart followed by brain, placenta, lung and pancreas. Weakly expressed in liver, kidney and skeletal muscle. Also expressed in islet and beta-cell insulinoma cell line.
• KEGG Pathway: Protein processing in endoplasmic reticulum (hsa04141)
• Reactome Pathway:
  Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs) (R-HSA-381426)
  Post-translational protein phosphorylation (R-HSA-8957275)
  XBP1(S) activates chaperone genes (R-HSA-381038)

Molecular Interaction Atlas (MIA) of This DOT

8 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Wolfram syndrome	DISN16XW	Definitive	Autosomal recessive	[1]
Wolfram syndrome 1	DISC2P61	Definitive	Autosomal recessive	[2]
Wolfram-like syndrome	DISI95DW	Definitive	Autosomal dominant	[1]
Autosomal dominant nonsyndromic hearing loss 6	DISBLMJP	Strong	Autosomal dominant	[3]
Cataract 41	DISDR8OQ	Strong	Autosomal dominant	[4]
Autosomal dominant nonsyndromic hearing loss	DISYC1G0	Supportive	Autosomal dominant	[5]
Early-onset nuclear cataract	DISGIHUY	Supportive	Autosomal dominant	[4]
Non-insulin dependent diabetes	DISK1O5Z	Limited	Unknown	[6]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Wolframin.	[7]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Wolframin.	[8]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Wolframin.	[9]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Wolframin.	[10]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Wolframin.	[11]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Wolframin.	[12]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of Wolframin.	[13]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone increases the expression of Wolframin.	[14]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Wolframin.	[15]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN increases the expression of Wolframin.	[18]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Wolframin.	[19]

3 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 increases the methylation of Wolframin.	[16]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Wolframin.	[17]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of Wolframin.	[17]

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] Diabetes and neurodegeneration in Wolfram syndrome: a multicenter study of phenotype and genotype. Diabetes Care. 2011 Jul;34(7):1503-10. doi: 10.2337/dc10-1937. Epub 2011 May 20.
• [3] Mutations in the Wolfram syndrome 1 gene (WFS1) are a common cause of low frequency sensorineural hearing loss. Hum Mol Genet. 2001 Oct 15;10(22):2501-8. doi: 10.1093/hmg/10.22.2501.
• [4] Wolfram gene (WFS1) mutation causes autosomal dominant congenital nuclear cataract in humans. Eur J Hum Genet. 2013 Dec;21(12):1356-60. doi: 10.1038/ejhg.2013.52. Epub 2013 Mar 27.
• [5] Genetic Hearing Loss Overview. 1999 Feb 14 [updated 2023 Sep 28]. 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.
• [6] WFS1 Gene-associated Diabetes Phenotypes and Identification of a Founder Mutation in Southern India. J Clin Endocrinol Metab. 2022 Apr 19;107(5):1328-1336. doi: 10.1210/clinem/dgac002.
• [7] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [8] 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.
• [9] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [10] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [11] High-throughput ectopic expression screen for tamoxifen resistance identifies an atypical kinase that blocks autophagy. Proc Natl Acad Sci U S A. 2011 Feb 1;108(5):2058-63.
• [12] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [13] Gene expression profile of human lymphoid CEM cells sensitive and resistant to glucocorticoid-evoked apoptosis. Genomics. 2003 Jun;81(6):543-55.
• [14] PPARgamma controls CD1d expression by turning on retinoic acid synthesis in developing human dendritic cells. J Exp Med. 2006 Oct 2;203(10):2351-62.
• [15] LSD1 activates a lethal prostate cancer gene network independently of its demethylase function. Proc Natl Acad Sci U S A. 2018 May 1;115(18):E4179-E4188.
• [16] 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.
• [17] 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.
• [18] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [19] Epigenetic influences of low-dose bisphenol A in primary human breast epithelial cells. Toxicol Appl Pharmacol. 2010 Oct 15;248(2):111-21.