Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTGDJ4US)

• DOT Name: Norrin (NDP)
• Synonyms: Norrie disease protein; X-linked exudative vitreoretinopathy 2 protein
• Gene Name: NDP
• Related Disease:
  Exudative vitreoretinopathy 2, X-linked
  Norrie disease
  Advanced cancer
  Alzheimer disease
  Breast cancer
  Breast carcinoma
  Childhood apraxia of speech
  Coats plus syndrome
  Coloboma
  Colorectal neoplasm
  Disorder of orbital region
  Esophageal squamous cell carcinoma
  Hepatocellular carcinoma
  Peters anomaly
  Plasma cell myeloma
  Retinitis
  Retinopathy
  Rhegmatogenous retinal detachment
  Schizophrenia
  Sclerocornea
  Vascular disease
  Vitreoretinal degeneration
  West syndrome
  Isolated congenital microcephaly
  Neurodevelopmental disorder
  Exudative vitreoretinopathy
  Persistent hyperplastic primary vitreous
  Blindness
  Hereditary hemochromatosis
• UniProt ID: NDP_HUMAN
• PDB ID: 4MY2; 5BPU; 5BQ8; 5BQB; 5BQC; 5BQE; 5CL1
• Pfam ID: PF00007
• Sequence:
  MRKHVLAASFSMLSLLVIMGDTDSKTDSSFIMDSDPRRCMRHHYVDSISHPLYKCSSKMV
  LLARCEGHCSQASRSEPLVSFSTVLKQPFRSSCHCCRPQTSKLKALRLRCSGGMRLTATY
  RYILSCHCEECNS
• Function: Activates the canonical Wnt signaling pathway through FZD4 and LRP5 coreceptor. Plays a central role in retinal vascularization by acting as a ligand for FZD4 that signals via stabilizing beta-catenin (CTNNB1) and activating LEF/TCF-mediated transcriptional programs. Acts in concert with TSPAN12 to activate FZD4 independently of the Wnt-dependent activation of FZD4, suggesting the existence of a Wnt-independent signaling that also promote accumulation the beta-catenin (CTNNB1). May be involved in a pathway that regulates neural cell differentiation and proliferation. Possible role in neuroectodermal cell-cell interaction.
• Tissue Specificity: Expressed in the outer nuclear, inner nuclear and ganglion cell layers of the retina, and in fetal and adult brain.

Molecular Interaction Atlas (MIA) of This DOT

29 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Exudative vitreoretinopathy 2, X-linked	DISQNNMA	Definitive	X-linked	[1]
Norrie disease	DISOCDDU	Definitive	X-linked	[2]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[3]
Alzheimer disease	DISF8S70	Strong	Altered Expression	[4]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[5]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[5]
Childhood apraxia of speech	DISIR974	Strong	Biomarker	[6]
Coats plus syndrome	DIS11ELA	Strong	Genetic Variation	[7]
Coloboma	DISP39N5	Strong	Genetic Variation	[8]
Colorectal neoplasm	DISR1UCN	Strong	Biomarker	[9]
Disorder of orbital region	DISH0ECJ	Strong	Biomarker	[8]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Biomarker	[10]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[11]
Peters anomaly	DISERK0M	Strong	Biomarker	[12]
Plasma cell myeloma	DIS0DFZ0	Strong	Biomarker	[13]
Retinitis	DISRWZEG	Strong	Biomarker	[14]
Retinopathy	DISB4B0F	Strong	Biomarker	[15]
Rhegmatogenous retinal detachment	DISLE27J	Strong	Biomarker	[16]
Schizophrenia	DISSRV2N	Strong	Biomarker	[17]
Sclerocornea	DIS7HV8A	Strong	Genetic Variation	[18]
Vascular disease	DISVS67S	Strong	Genetic Variation	[19]
Vitreoretinal degeneration	DISVPRKD	Strong	Genetic Variation	[20]
West syndrome	DISLIAU9	Strong	Genetic Variation	[21]
Isolated congenital microcephaly	DISUXHZ6	moderate	Genetic Variation	[22]
Neurodevelopmental disorder	DIS372XH	moderate	Genetic Variation	[23]
Exudative vitreoretinopathy	DISWN0TG	Supportive	Autosomal dominant	[24]
Persistent hyperplastic primary vitreous	DISABPH6	Supportive	Autosomal dominant	[24]
Blindness	DISTIM10	Limited	Genetic Variation	[25]
Hereditary hemochromatosis	DISVG5MT	Limited	Biomarker	[26]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Norrin (NDP).	[27]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Norrin (NDP).	[34]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Norrin (NDP).	[28]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Norrin (NDP).	[29]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of Norrin (NDP).	[30]
Panobinostat	DM58WKG	Approved	Panobinostat decreases the expression of Norrin (NDP).	[31]
Mifepristone	DMGZQEF	Approved	Mifepristone decreases the expression of Norrin (NDP).	[32]
3,4-Dihydroxycinnamic Acid	DMVZL26	Phase 4	3,4-Dihydroxycinnamic Acid increases the expression of Norrin (NDP).	[33]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Norrin (NDP).	[31]
Belinostat	DM6OC53	Phase 2	Belinostat decreases the expression of Norrin (NDP).	[31]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Norrin (NDP).	[35]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Norrin (NDP).	[36]
geraniol	DMS3CBD	Investigative	geraniol decreases the expression of Norrin (NDP).	[37]

References

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• [2] 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.
• [3] Expression of p53 and NDP-K/nm23 in gastric carcinomas--association with metastasis and clinicopathologic parameters.J Korean Med Sci. 1995 Dec;10(6):406-13. doi: 10.3346/jkms.1995.10.6.406.
• [4] l-Dopa and dopamine conjugated naphthalenediimides modulate amyloid toxicity.Org Biomol Chem. 2018 Nov 7;16(41):7682-7692. doi: 10.1039/c8ob01691g. Epub 2018 Oct 4.
• [5] NDP-K/nm23 expression in human breast cancer in relation to relapse, survival, and other prognostic factors: an immunohistochemical study.J Pathol. 1994 Jan;172(1):27-34. doi: 10.1002/path.1711720107.
• [6] Interventions for childhood apraxia of speech.Cochrane Database Syst Rev. 2018 May 30;5(5):CD006278. doi: 10.1002/14651858.CD006278.pub3.
• [7] Cerebroretinal microangiopathy with calcifications and cysts associated with CTC1 and NDP mutations.J Child Neurol. 2013 Dec;28(12):1702-8. doi: 10.1177/0883073812467849. Epub 2012 Dec 5.
• [8] A case of exudative vitreoretinopathy and chorioretinal coloboma associated with microcephaly in a female with contiguous Xp11.3-11.4 deletion.Ophthalmic Genet. 2018 Jun;39(3):396-398. doi: 10.1080/13816810.2018.1443342. Epub 2018 Apr 4.
• [9] A novel signaling pathway regulates colon cancer angiogenesis through Norrin.Sci Rep. 2014 Jul 9;4:5630. doi: 10.1038/srep05630.
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• [11] Nm23/NDP kinases in hepatocellular carcinoma.J Bioenerg Biomembr. 2006 Aug;38(3-4):169-75. doi: 10.1007/s10863-006-9031-4.
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• [14] Cystoid edema, neovascularization and inflammatory processes in the murine Norrin-deficient retina.Sci Rep. 2018 Apr 13;8(1):5970. doi: 10.1038/s41598-018-24476-y.
• [15] Germline Mutations in CTNNB1 Associated With Syndromic FEVR or Norrie Disease.Invest Ophthalmol Vis Sci. 2019 Jan 2;60(1):93-97. doi: 10.1167/iovs.18-25142.
• [16] CLINICAL FEATURES OF AFFECTED AND UNDETACHED FELLOW EYES IN PATIENTS WITH FEVR-ASSOCIATED RHEGMATOGENOUS RETINAL DETACHMENT.Retina. 2017 Mar;37(3):585-591. doi: 10.1097/IAE.0000000000001171.
• [17] Investigating association of four gene regions (GABRB3, MAOB, PAH, and SLC6A4) with five symptoms in schizophrenia.Psychiatry Res. 2012 Jul 30;198(2):202-6. doi: 10.1016/j.psychres.2011.12.035. Epub 2012 Mar 12.
• [18] Novel mutations in PAX6, OTX2 and NDP in anophthalmia, microphthalmia and coloboma.Eur J Hum Genet. 2016 Apr;24(4):535-41. doi: 10.1038/ejhg.2015.155. Epub 2015 Jul 1.
• [19] A novel NDP mutation in an infant with unilateral persistent fetal vasculature and retinal vasculopathy.Ophthalmic Genet. 2009 Jun;30(2):99-102. doi: 10.1080/13816810802705755.
• [20] Wnt-Spectrum Vitreoretinopathy Masquerading as Congenital Toxoplasmosis.Ophthalmic Surg Lasers Imaging Retina. 2018 Jun 1;49(6):446-450. doi: 10.3928/23258160-20180601-10.
• [21] A novel missense mutation in the NDP gene in a child with Norrie disease and severe neurological involvement including infantile spasms.Am J Med Genet A. 2007 May 1;143A(9):921-4. doi: 10.1002/ajmg.a.31531.
• [22] Phenotypic overlap between familial exudative vitreoretinopathy and microcephaly, lymphedema, and chorioretinal dysplasia caused by KIF11 mutations.JAMA Ophthalmol. 2014 Dec;132(12):1393-9. doi: 10.1001/jamaophthalmol.2014.2814.
• [23] Norrie disease gene: characterization of deletions and possible function.Genomics. 1993 May;16(2):533-5. doi: 10.1006/geno.1993.1224.
• [24] NDP-Related Retinopathies. 1999 Jul 30 [updated 2023 Mar 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.
• [25] Long-term consequences of developmental vascular defects on retinal vessel homeostasis and function in a mouse model of Norrie disease.PLoS One. 2017 Jun 2;12(6):e0178753. doi: 10.1371/journal.pone.0178753. eCollection 2017.
• [26] Hedgehog regulates Norrie disease protein to drive neural progenitor self-renewal.Hum Mol Genet. 2013 Mar 1;22(5):1005-16. doi: 10.1093/hmg/dds505. Epub 2012 Nov 30.
• [27] 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.
• [28] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [29] Identification of transcriptome signatures and biomarkers specific for potential developmental toxicants inhibiting human neural crest cell migration. Arch Toxicol. 2016 Jan;90(1):159-80.
• [30] Progesterone regulation of implantation-related genes: new insights into the role of oestrogen. Cell Mol Life Sci. 2007 Apr;64(7-8):1009-32.
• [31] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [32] Mifepristone induced progesterone withdrawal reveals novel regulatory pathways in human endometrium. Mol Hum Reprod. 2007 Sep;13(9):641-54.
• [33] The genome-wide expression profile of Scrophularia ningpoensis-treated thapsigargin-stimulated U-87MG cells. Neurotoxicology. 2009 May;30(3):368-76.
• [34] 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.
• [35] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
• [36] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [37] Geraniol suppresses prostate cancer growth through down-regulation of E2F8. Cancer Med. 2016 Oct;5(10):2899-2908.