Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTTV05B1)

• DOT Name: Homeobox protein OTX2 (OTX2)
• Synonyms: Orthodenticle homolog 2
• Gene Name: OTX2
• Related Disease:
  Ependymoma
  Syndromic microphthalmia type 5
  Adenocarcinoma
  Age-related macular degeneration
  Agnathia-otocephaly complex
  Bipolar disorder
  Brain cancer
  Breast cancer
  Breast carcinoma
  Carcinoma
  Classic Hodgkin lymphoma
  Coloboma
  Craniofacial microsomia
  Depression
  Disorder of orbital region
  Inherited retinal dystrophy
  Kallmann syndrome
  Leber congenital amaurosis
  Lung adenocarcinoma
  Medulloblastoma
  Pituitary hormone deficiency, combined, 1
  Pituitary hormone deficiency, combined, 6
  Retinitis pigmentosa
  Retinopathy
  Advanced cancer
  Microphthalmia
  Neurodegenerative disease
  Squamous cell carcinoma
  Combined pituitary hormone deficiencies, genetic form
  Isolated anophthalmia-microphthalmia syndrome
  Patterned macular dystrophy
  Septooptic dysplasia
  Intellectual disability
  Pituitary dwarfism
  Hypopituitarism
  Kennedy disease
  Neoplasm
  Pituitary stalk interruption syndrome
  Proliferative vitreoretinopathy
  Retinoblastoma
• UniProt ID: OTX2_HUMAN
• Pfam ID: PF00046 ; PF03529
• Sequence:
  MMSYLKQPPYAVNGLSLTTSGMDLLHPSVGYPATPRKQRRERTTFTRAQLDVLEALFAKT
  RYPDIFMREEVALKINLPESRVQVWFKNRRAKCRQQQQQQQNGGQNKVRPAKKKTSPARE
  VSSESGTSGQFTPPSSTSVPTIASSSAPVSIWSPASISPLSDPLSTSSSCMQRSYPMTYT
  QASGYSQGYAGSTSYFGGMDCGSYLTPMHHQLPGPGATLSPMGTNAVTSHLNQSPASLST
  QGYGASSLGFNSTTDCLDYKDQTASWKLNFNADCLDYKDQTSSWKFQVL
• Function: Transcription factor probably involved in the development of the brain and the sense organs. Can bind to the bicoid/BCD target sequence (BTS): 5'-TCTAATCCC-3'.
• Reactome Pathway:
  Formation of the posterior neural plate (R-HSA-9832991)
  Formation of the anterior neural plate (R-HSA-9823739)

Molecular Interaction Atlas (MIA) of This DOT

40 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Ependymoma	DISUMRNZ	Definitive	Biomarker	[1]
Syndromic microphthalmia type 5	DISMNE1H	Definitive	Autosomal dominant	[2]
Adenocarcinoma	DIS3IHTY	Strong	Altered Expression	[3]
Age-related macular degeneration	DIS0XS2C	Strong	Biomarker	[4]
Agnathia-otocephaly complex	DISFA33B	Strong	Genetic Variation	[5]
Bipolar disorder	DISAM7J2	Strong	Genetic Variation	[6]
Brain cancer	DISBKFB7	Strong	Altered Expression	[7]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[8]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[8]
Carcinoma	DISH9F1N	Strong	Biomarker	[3]
Classic Hodgkin lymphoma	DISV1LU6	Strong	Altered Expression	[9]
Coloboma	DISP39N5	Strong	Genetic Variation	[10]
Craniofacial microsomia	DISYHJ2P	Strong	Biomarker	[11]
Depression	DIS3XJ69	Strong	Biomarker	[12]
Disorder of orbital region	DISH0ECJ	Strong	Biomarker	[13]
Inherited retinal dystrophy	DISGGL77	Strong	Genetic Variation	[14]
Kallmann syndrome	DISO3HDG	Strong	GermlineCausalMutation	[15]
Leber congenital amaurosis	DISMGH8F	Strong	Genetic Variation	[14]
Lung adenocarcinoma	DISD51WR	Strong	Altered Expression	[16]
Medulloblastoma	DISZD2ZL	Strong	Altered Expression	[17]
Pituitary hormone deficiency, combined, 1	DISVFM4T	Strong	GermlineCausalMutation	[18]
Pituitary hormone deficiency, combined, 6	DISAKZ49	Strong	Autosomal dominant	[18]
Retinitis pigmentosa	DISCGPY8	Strong	Altered Expression	[4]
Retinopathy	DISB4B0F	Strong	Biomarker	[19]
Advanced cancer	DISAT1Z9	moderate	Biomarker	[20]
Microphthalmia	DISGEBES	moderate	Genetic Variation	[21]
Neurodegenerative disease	DISM20FF	moderate	Biomarker	[22]
Squamous cell carcinoma	DISQVIFL	moderate	Biomarker	[23]
Combined pituitary hormone deficiencies, genetic form	DISW6YL6	Supportive	Autosomal dominant	[18]
Isolated anophthalmia-microphthalmia syndrome	DISA55ZA	Supportive	Autosomal dominant	[24]
Patterned macular dystrophy	DISWIXVD	Supportive	Autosomal dominant	[19]
Septooptic dysplasia	DISXYR1H	Supportive	Autosomal dominant	[25]
Intellectual disability	DISMBNXP	Disputed	Biomarker	[26]
Pituitary dwarfism	DISI019B	Disputed	Biomarker	[27]
Hypopituitarism	DIS1QT3G	Limited	Genetic Variation	[28]
Kennedy disease	DISXZVM1	Limited	Biomarker	[29]
Neoplasm	DISZKGEW	Limited	Genetic Variation	[3]
Pituitary stalk interruption syndrome	DISGSN5T	Limited	Biomarker	[30]
Proliferative vitreoretinopathy	DISZTEK1	Limited	Biomarker	[31]
Retinoblastoma	DISVPNPB	Limited	Biomarker	[32]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Homeobox protein OTX2 (OTX2).	[33]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Homeobox protein OTX2 (OTX2).	[34]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Homeobox protein OTX2 (OTX2).	[35]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Homeobox protein OTX2 (OTX2).	[36]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil decreases the expression of Homeobox protein OTX2 (OTX2).	[37]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Homeobox protein OTX2 (OTX2).	[39]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Homeobox protein OTX2 (OTX2).	[33]
CHIR-98014	DMVEBT6	Investigative	CHIR-98014 decreases the expression of Homeobox protein OTX2 (OTX2).	[33]

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 affects the methylation of Homeobox protein OTX2 (OTX2).	[38]

References

• [1] Molecular heterogeneity and CXorf67 alterations in posterior fossa group A (PFA) ependymomas.Acta Neuropathol. 2018 Aug;136(2):211-226. doi: 10.1007/s00401-018-1877-0. Epub 2018 Jun 16.
• [2] OTX2 mutation in a patient with anophthalmia, short stature, and partial growth hormone deficiency: functional studies using the IRBP, HESX1, and POU1F1 promoters. J Clin Endocrinol Metab. 2008 Oct;93(10):3697-702. doi: 10.1210/jc.2008-0720. Epub 2008 Jul 15.
• [3] Identification of OTX1 and OTX2 As Two Possible Molecular Markers for Sinonasal Carcinomas and Olfactory Neuroblastomas.J Vis Exp. 2019 Feb 28;(144). doi: 10.3791/56880.
• [4] Otx2-Genetically Modified Retinal Pigment Epithelial Cells Rescue Photoreceptors after Transplantation.Mol Ther. 2018 Jan 3;26(1):219-237. doi: 10.1016/j.ymthe.2017.09.007. Epub 2017 Sep 8.
• [5] Agnathia-otocephaly complex and asymmetric velopharyngeal insufficiency due to an in-frame duplication in OTX2.J Hum Genet. 2015 Apr;60(4):199-202. doi: 10.1038/jhg.2014.122. Epub 2015 Jan 15.
• [6] Polymorphisms in the homeobox gene OTX2 may be a risk factor for bipolar disorder.Am J Med Genet B Neuropsychiatr Genet. 2007 Dec 5;144B(8):1083-6. doi: 10.1002/ajmg.b.30523.
• [7] OTX2 directly activates cell cycle genes and inhibits differentiation in medulloblastoma cells.Int J Cancer. 2012 Jul 15;131(2):E21-32. doi: 10.1002/ijc.26474. Epub 2011 Nov 8.
• [8] Screening of significantly hypermethylated genes in breast cancer using microarray-based methylated-CpG island recovery assay and identification of their expression levels.Int J Oncol. 2012 Aug;41(2):629-38. doi: 10.3892/ijo.2012.1464. Epub 2012 May 8.
• [9] Aberrantly Expressed OTX Homeobox Genes Deregulate B-Cell Differentiation in Hodgkin Lymphoma.PLoS One. 2015 Sep 25;10(9):e0138416. doi: 10.1371/journal.pone.0138416. eCollection 2015.
• [10] The genetic architecture of microphthalmia, anophthalmia and coloboma. Eur J Med Genet. 2014 Aug;57(8):369-80. doi: 10.1016/j.ejmg.2014.05.002. Epub 2014 May 22.
• [11] OTX2 duplication is implicated in hemifacial microsomia.PLoS One. 2014 May 9;9(5):e96788. doi: 10.1371/journal.pone.0096788. eCollection 2014.
• [12] Methylation in OTX2 and related genes, maltreatment, and depression in children.Neuropsychopharmacology. 2018 Oct;43(11):2204-2211. doi: 10.1038/s41386-018-0157-y. Epub 2018 Jul 21.
• [13] MLGA: a cost-effective approach to the diagnosis of gene deletions in eye development anomalies.Mol Vis. 2009 Jul 28;15:1445-8.
• [14] A rare de novo nonsense mutation in OTX2 causes early onset retinal dystrophy and pituitary dysfunction.Mol Vis. 2009 Nov 21;15:2442-7.
• [15] New insights into septo-optic dysplasia.Pril (Makedon Akad Nauk Umet Odd Med Nauki). 2014;35(1):123-7.
• [16] DMBX1 promotes tumor proliferation and regulates cell cycle progression via repressing OTX2-mediated transcription of p21 in lung adenocarcinoma cell.Cancer Lett. 2019 Jul 1;453:45-56. doi: 10.1016/j.canlet.2019.03.045. Epub 2019 Mar 27.
• [17] OTX1 and OTX2 Genes in Medulloblastoma.World Neurosurg. 2019 Jul;127:e58-e64. doi: 10.1016/j.wneu.2019.02.013. Epub 2019 Feb 21.
• [18] A novel dominant negative mutation of OTX2 associated with combined pituitary hormone deficiency. J Clin Endocrinol Metab. 2008 Nov;93(11):4351-9. doi: 10.1210/jc.2008-1189. Epub 2008 Aug 26.
• [19] OTX2 mutations cause autosomal dominant pattern dystrophy of the retinal pigment epithelium. J Med Genet. 2014 Dec;51(12):797-805. doi: 10.1136/jmedgenet-2014-102620. Epub 2014 Oct 7.
• [20] OTX2 Activity at Distal Regulatory Elements Shapes the Chromatin Landscape of Group 3 Medulloblastoma.Cancer Discov. 2017 Mar;7(3):288-301. doi: 10.1158/2159-8290.CD-16-0844. Epub 2017 Feb 17.
• [21] Homozygous variant in OTX2 and possible genetic modifiers identified in a patient with combined pituitary hormone deficiency, ocular involvement, myopathy, ataxia, and mitochondrial impairment.Am J Med Genet A. 2019 May;179(5):827-831. doi: 10.1002/ajmg.a.61092. Epub 2019 Feb 17.
• [22] The transcription factor orthodenticle homeobox 2 influences axonal projections and vulnerability of midbrain dopaminergic neurons.Brain. 2010 Jul;133(Pt 7):2022-31. doi: 10.1093/brain/awq142. Epub 2010 Jun 23.
• [23] DNA methylation biomarkers for lung cancer.Tumour Biol. 2012 Apr;33(2):287-96. doi: 10.1007/s13277-011-0282-2. Epub 2011 Dec 6.
• [24] Molecular findings and clinical data in a cohort of 150 patients with anophthalmia/microphthalmia. Clin Genet. 2014 Oct;86(4):326-34. doi: 10.1111/cge.12275. Epub 2013 Oct 7.
• [25] Septo-optic dysplasia and other midline defects: the role of transcription factors: HESX1 and beyond. Best Pract Res Clin Endocrinol Metab. 2011 Feb;25(1):115-24. doi: 10.1016/j.beem.2010.06.008.
• [26] New insights into the phenotypic spectrum of 14q22q23 deletions: a case report and literature review.BMC Med Genomics. 2018 Sep 29;11(1):87. doi: 10.1186/s12920-018-0405-3.
• [27] A novel OTX2 mutation in a patient with combined pituitary hormone deficiency, pituitary malformation, and an underdeveloped left optic nerve.Eur J Endocrinol. 2012 Sep;167(3):441-52. doi: 10.1530/EJE-12-0333. Epub 2012 Jun 19.
• [28] Genetic diagnosis of congenital hypopituitarism by a target gene panel: novel pathogenic variants in GLI2, OTX2 and GHRHR.Endocr Connect. 2019 May 1;8(5):590-595. doi: 10.1530/EC-19-0085.
• [29] Characterization of a novel OTX2-driven stem cell program in Group 3 and Group 4 medulloblastoma.Mol Oncol. 2018 Apr;12(4):495-513. doi: 10.1002/1878-0261.12177. Epub 2018 Mar 1.
• [30] Pituitary Stalk Interruption Syndrome: From Clinical Findings to Pathogenesis.J Neuroendocrinol. 2017 Jan;29(1). doi: 10.1111/jne.12451.
• [31] Expression of VEGF-A, Otx homeobox and p53 family genes in proliferative vitreoretinopathy.Mediators Inflamm. 2013;2013:857380. doi: 10.1155/2013/857380. Epub 2013 Oct 21.
• [32] PIWI-like protein, HIWI2 is aberrantly expressed in retinoblastoma cells and affects cell-cycle potentially through OTX2.Cell Mol Biol Lett. 2017 Aug 29;22:17. doi: 10.1186/s11658-017-0048-y. eCollection 2017.
• [33] Epigenetic changes and disturbed neural development in a human embryonic stem cell-based model relating to the fetal valproate syndrome. Hum Mol Genet. 2012 Sep 15;21(18):4104-14. doi: 10.1093/hmg/dds239. Epub 2012 Jun 20.
• [34] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [35] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [36] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [37] 5-Fluorouracil inhibits neural differentiation via Mfn1/2 reduction in human induced pluripotent stem cells. J Toxicol Sci. 2018;43(12):727-734. doi: 10.2131/jts.43.727.
• [38] 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.
• [39] Transcriptomic?pathway?and?benchmark dose analysis of Bisphenol A, Bisphenol S, Bisphenol F, and 3,3',5,5'-Tetrabromobisphenol A in H9 human embryonic stem cells. Toxicol In Vitro. 2021 Apr;72:105097. doi: 10.1016/j.tiv.2021.105097. Epub 2021 Jan 18.