Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTO3GBHQ)

• DOT Name: Photoreceptor-specific nuclear receptor (NR2E3)
• Synonyms: Nuclear receptor subfamily 2 group E member 3; Retina-specific nuclear receptor
• Gene Name: NR2E3
• Related Disease:
  Enhanced S-cone syndrome
  Retinitis pigmentosa 37
  Achromatopsia
  Advanced cancer
  Blue cone monochromacy
  Breast cancer
  Breast carcinoma
  Cardiac failure
  Cholangiocarcinoma
  Complex regional pain syndrome type 1
  Congenital stationary night blindness 2A
  Congestive heart failure
  Estrogen-receptor positive breast cancer
  Glomerulonephritis
  Inherited retinal dystrophy
  Leber congenital amaurosis 1
  Myocardial infarction
  Neoplasm
  Night blindness
  Retinal degeneration
  Stargardt disease
  Age-related macular degeneration
  Bacterial infection
  Retinopathy
  Goldmann-Favre syndrome
  Retinitis pigmentosa
  Blindness
  Carcinoma of liver and intrahepatic biliary tract
  Liver cancer
• UniProt ID: NR2E3_HUMAN
• PDB ID: 4LOG
• Pfam ID: PF00104 ; PF00105
• Sequence:
  METRPTALMSSTVAAAAPAAGAASRKESPGRWGLGEDPTGVSPSLQCRVCGDSSSGKHYG
  IYACNGCSGFFKRSVRRRLIYRCQVGAGMCPVDKAHRNQCQACRLKKCLQAGMNQDAVQN
  ERQPRSTAQVHLDSMESNTESRPESLVAPPAPAGRSPRGPTPMSAARALGHHFMASLITA
  ETCAKLEPEDADENIDVTSNDPEFPSSPYSSSSPCGLDSIHETSARLLFMAVKWAKNLPV
  FSSLPFRDQVILLEEAWSELFLLGAIQWSLPLDSCPLLAPPEASAAGGAQGRLTLASMET
  RVLQETISRFRALAVDPTEFACMKALVLFKPETRGLKDPEHVEALQDQSQVMLSQHSKAH
  HPSQPVRFGKLLLLLPSLRFITAERIELLFFRKTIGNTPMEKLLCDMFKN
• Function: Orphan nuclear receptor of retinal photoreceptor cells. Transcriptional factor that is an activator of rod development and repressor of cone development. Binds the promoter region of a number of rod- and cone-specific genes, including rhodopsin, M- and S-opsin and rod-specific phosphodiesterase beta subunit. Enhances rhodopsin expression. Represses M- and S-cone opsin expression.
• Tissue Specificity: Eye specific; found solely in the outer nuclear layer of the adult neurosensory retina, where the nuclei of cone and rod photoreceptors reside.
• Reactome Pathway: Nuclear Receptor transcription pathway (R-HSA-383280)

Molecular Interaction Atlas (MIA) of This DOT

29 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Enhanced S-cone syndrome	DIS2IWS3	Definitive	Autosomal recessive	[1]
Retinitis pigmentosa 37	DIS5Y7CF	Definitive	Autosomal dominant	[2]
Achromatopsia	DISKL51I	Strong	Genetic Variation	[3]
Advanced cancer	DISAT1Z9	Strong	Genetic Variation	[4]
Blue cone monochromacy	DISYV7KB	Strong	Genetic Variation	[5]
Breast cancer	DIS7DPX1	Strong	Biomarker	[6]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[6]
Cardiac failure	DISDC067	Strong	Biomarker	[7]
Cholangiocarcinoma	DIS71F6X	Strong	Altered Expression	[8]
Complex regional pain syndrome type 1	DISEUIQP	Strong	Biomarker	[9]
Congenital stationary night blindness 2A	DISA57KI	Strong	Genetic Variation	[3]
Congestive heart failure	DIS32MEA	Strong	Biomarker	[7]
Estrogen-receptor positive breast cancer	DIS1H502	Strong	Altered Expression	[10]
Glomerulonephritis	DISPZIQ3	Strong	Biomarker	[11]
Inherited retinal dystrophy	DISGGL77	Strong	Biomarker	[12]
Leber congenital amaurosis 1	DISY2B33	Strong	Genetic Variation	[3]
Myocardial infarction	DIS655KI	Strong	Biomarker	[7]
Neoplasm	DISZKGEW	Strong	Biomarker	[13]
Night blindness	DIS335K9	Strong	Genetic Variation	[12]
Retinal degeneration	DISM1JHQ	Strong	Biomarker	[1]
Stargardt disease	DISPXOTO	Strong	Biomarker	[14]
Age-related macular degeneration	DIS0XS2C	moderate	Biomarker	[15]
Bacterial infection	DIS5QJ9S	moderate	Biomarker	[16]
Retinopathy	DISB4B0F	moderate	Genetic Variation	[17]
Goldmann-Favre syndrome	DIS629CF	Supportive	Autosomal recessive	[18]
Retinitis pigmentosa	DISCGPY8	Supportive	Autosomal dominant	[19]
Blindness	DISTIM10	Limited	Genetic Variation	[20]
Carcinoma of liver and intrahepatic biliary tract	DIS8WA0W	Limited	Biomarker	[21]
Liver cancer	DISDE4BI	Limited	Biomarker	[21]

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 Photoreceptor-specific nuclear receptor (NR2E3).	[22]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Photoreceptor-specific nuclear receptor (NR2E3).	[25]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Photoreceptor-specific nuclear receptor (NR2E3).	[23]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Photoreceptor-specific nuclear receptor (NR2E3).	[24]

References

• [1] Shared mutations in NR2E3 in enhanced S-cone syndrome, Goldmann-Favre syndrome, and many cases of clumped pigmentary retinal degeneration. Arch Ophthalmol. 2003 Sep;121(9):1316-23. doi: 10.1001/archopht.121.9.1316.
• [2] Recurrent mutation in the first zinc finger of the orphan nuclear receptor NR2E3 causes autosomal dominant retinitis pigmentosa. Am J Hum Genet. 2007 Jul;81(1):147-57. doi: 10.1086/518426. Epub 2007 May 24.
• [3] Infantile and childhood retinal blindness: a molecular perspective (The Franceschetti Lecture).Ophthalmic Genet. 2002 Jun;23(2):71-97. doi: 10.1076/opge.23.2.71.2214.
• [4] Orphan nuclear receptor PNR/NR2E3 stimulates p53 functions by enhancing p53 acetylation.Mol Cell Biol. 2012 Jan;32(1):26-35. doi: 10.1128/MCB.05513-11. Epub 2011 Oct 24.
• [5] Novel mutations in the OPN1LW and NR2R3 genes in a patient with blue cone monochromacy.Ophthalmic Genet. 2019 Feb;40(1):43-48. doi: 10.1080/13816810.2018.1561902. Epub 2019 Jan 7.
• [6] The contribution of SIPA1 and RRP1B germline polymorphisms to breast cancer phenotype, lymph node status and survival in a group of Lithuanian young breast cancer patients.Biomarkers. 2016;21(4):363-70. doi: 10.3109/1354750X.2016.1141989. Epub 2016 Feb 22.
• [7] Ribonucleotide reductase-mediated increase in dATP improves cardiac performance via myosin activation in a large animal model of heart failure.Eur J Heart Fail. 2015 Aug;17(8):772-81. doi: 10.1002/ejhf.270. Epub 2015 Apr 15.
• [8] Gene expression analysis for predicting gemcitabine resistance in human cholangiocarcinoma.J Hepatobiliary Pancreat Sci. 2011 Sep;18(5):700-11. doi: 10.1007/s00534-011-0376-7.
• [9] Evaluation Through Transcutaneous Tissue Oximetry (Near Infrared Spectroscopy) of Spinal Cord Stimulation in Patients With Complex Regional Pain Syndrome Type I.Neuromodulation. 2020 Jul;23(5):698-703. doi: 10.1111/ner.12931. Epub 2019 Feb 20.
• [10] Reconstruction of nuclear receptor network reveals that NR2E3 is a novel upstream regulator of ESR1 in breast cancer.EMBO Mol Med. 2012 Jan;4(1):52-67. doi: 10.1002/emmm.201100187. Epub 2011 Dec 15.
• [11] Urinary podocyte mRNA is a potent biomarker of anti-neutrophil cytoplasmic antibody-associated glomerulonephritis.Clin Exp Nephrol. 2020 Mar;24(3):242-252. doi: 10.1007/s10157-019-01823-5. Epub 2019 Nov 25.
• [12] Novel clinical findings in autosomal recessive NR2E3-related retinal dystrophy.Graefes Arch Clin Exp Ophthalmol. 2019 Jan;257(1):9-22. doi: 10.1007/s00417-018-4161-z. Epub 2018 Oct 15.
• [13] IL-13R2 mediates PNR-induced migration and metastasis in ER-negative breast cancer.Oncogene. 2015 Mar 19;34(12):1596-607. doi: 10.1038/onc.2014.53. Epub 2014 Apr 21.
• [14] The Marshall M. Parks memorial lecture: making sense of early-onset childhood retinal dystrophies--the clinical phenotype of Leber congenital amaurosis.Br J Ophthalmol. 2010 Oct;94(10):1281-7. doi: 10.1136/bjo.2009.165654. Epub 2009 Oct 12.
• [15] FLT1 genetic variation predisposes to neovascular AMD in ethnically diverse populations and alters systemic FLT1 expression.Invest Ophthalmol Vis Sci. 2014 May 8;55(6):3543-54. doi: 10.1167/iovs.14-14047.
• [16] Ribonucleotide reductase NrdR as a novel regulator for motility and chemotaxis during adherent-invasive Escherichia coli infection.Infect Immun. 2015 Apr;83(4):1305-17. doi: 10.1128/IAI.02772-14. Epub 2015 Jan 20.
• [17] Heterodimers of photoreceptor-specific nuclear receptor (PNR/NR2E3) and peroxisome proliferator-activated receptor- (PPAR) are disrupted by retinal disease-associated mutations.Cell Death Dis. 2017 Mar 16;8(3):e2677. doi: 10.1038/cddis.2017.98.
• [18] Mutation of a nuclear receptor gene, NR2E3, causes enhanced S cone syndrome, a disorder of retinal cell fate. Nat Genet. 2000 Feb;24(2):127-31. doi: 10.1038/72777.
• [19] Nonsyndromic Retinitis Pigmentosa Overview. 2000 Aug 4 [updated 2023 Apr 6]. 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.
• [20] Cone Vision Changes in the Enhanced S-Cone Syndrome Caused by NR2E3 Gene Mutations.Invest Ophthalmol Vis Sci. 2018 Jul 2;59(8):3209-3219. doi: 10.1167/iovs.18-24518.
• [21] Loss of NR2E3 represses AHR by LSD1 reprogramming, is associated with poor prognosis in liver cancer.Sci Rep. 2017 Sep 6;7(1):10662. doi: 10.1038/s41598-017-11106-2.
• [22] 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.
• [23] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [24] Deregulation of NR2E3, an orphan nuclear receptor, by benzo(a)pyrene-induced oxidative stress is associated with histone modification status change of the estrogen receptor gene promoter. Toxicol Lett. 2015 Sep 17;237(3):228-36. doi: 10.1016/j.toxlet.2015.06.1708. Epub 2015 Jul 3.
• [25] 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.