Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTE2KT8P)

DOT Name	Pituitary homeobox 3 (PITX3)
Synonyms	Homeobox protein PITX3; Paired-like homeodomain transcription factor 3
Gene Name	PITX3
Related Disease	Anterior segment dysgenesis 1 ( ) Cataract ( ) Cataract 11 multiple types ( ) Cataract 9 multiple types ( ) Disorder of orbital region ( ) Amyloidosis ( ) Anterior segment dysgenesis ( ) Cardiac failure ( ) Cataract 20 multiple types ( ) Classic Hodgkin lymphoma ( ) Congestive heart failure ( ) Dementia ( ) Depression ( ) Huntington disease ( ) Myocardial infarction ( ) Nervous system disease ( ) Non-alcoholic fatty liver disease ( ) Obesity ( ) Obstructive sleep apnea ( ) Prostate cancer ( ) Prostate neoplasm ( ) Bloom syndrome ( ) Neuroblastoma ( ) Peters anomaly ( ) Cataract-glaucoma syndrome ( ) Early-onset posterior polar cataract ( ) Intellectual disability ( ) Advanced cancer ( ) Arteriosclerosis ( ) Atherosclerosis ( ) Atrial septal defect ( ) Autism spectrum disorder ( ) Chronic obstructive pulmonary disease ( ) Erectile dysfunction ( ) Microphthalmia ( ) Schizophrenia ( ) Young-onset Parkinson disease ( )
UniProt ID	PITX3_HUMAN
3D Structure	Download 2D Sequence (FASTA) Download 3D Structure (PDB) Download
Pfam ID	PF00046 ; PF03826
Sequence	MEFGLLSEAEARSPALSLSDAGTPHPQLPEHGCKGQEHSDSEKASASLPGGSPEDGSLKK KQRRQRTHFTSQQLQELEATFQRNRYPDMSTREEIAVWTNLTEARVRVWFKNRRAKWRKR ERSQQAELCKGSFAAPLGGLVPPYEEVYPGYSYGNWPPKALAPPLAAKTFPFAFNSVNVG PLASQPVFSPPSSIAASMVPSAAAAPGTVPGPGALQGLGGGPPGLAPAAVSSGAVSCPYA SAAAAAAAAASSPYVYRDPCNSSLASLRLKAKQHASFSYPAVHGPPPAANLSPCQYAVER PV
Function	Transcriptional regulator which is important for the differentiation and maintenance of meso-diencephalic dopaminergic (mdDA) neurons during development. In addition to its importance during development, it also has roles in the long-term survival and maintenance of the mdDA neurons. Activates NR4A2/NURR1-mediated transcription of genes such as SLC6A3, SLC18A2, TH and DRD2 which are essential for development of mdDA neurons. Acts by decreasing the interaction of NR4A2/NURR1 with the corepressor NCOR2/SMRT which acts through histone deacetylases (HDACs) to keep promoters of NR4A2/NURR1 target genes in a repressed deacetylated state. Essential for the normal lens development and differentiation. Plays a critical role in the maintenance of mitotic activity of lens epithelial cells, fiber cell differentiation and in the control of the temporal and spatial activation of fiber cell-specific crystallins. Positively regulates FOXE3 expression and negatively regulates PROX1 in the anterior lens epithelium, preventing activation of CDKN1B/P27Kip1 and CDKN1C/P57Kip2 and thus maintains lens epithelial cells in cell cycle.
Tissue Specificity	Highly expressed in developing eye lens.

Molecular Interaction Atlas (MIA) of This DOT

37 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance
Anterior segment dysgenesis 1	DIS4K5KH	Definitive	Autosomal dominant	[1]
Cataract	DISUD7SL	Definitive	Biomarker	[2]
Cataract 11 multiple types	DISRGIJ7	Definitive	Autosomal dominant	[3]
Cataract 9 multiple types	DIS9JQ8P	Definitive	Autosomal dominant	[3]
Disorder of orbital region	DISH0ECJ	Definitive	Biomarker	[4]
Amyloidosis	DISHTAI2	Strong	Biomarker	[5]
Anterior segment dysgenesis	DIS12OKO	Strong	Genetic Variation	[6]
Cardiac failure	DISDC067	Strong	Biomarker	[7]
Cataract 20 multiple types	DISN0IHS	Strong	Biomarker	[8]
Classic Hodgkin lymphoma	DISV1LU6	Strong	Biomarker	[9]
Congestive heart failure	DIS32MEA	Strong	Biomarker	[7]
Dementia	DISXL1WY	Strong	Genetic Variation	[10]
Depression	DIS3XJ69	Strong	Biomarker	[11]
Huntington disease	DISQPLA4	Strong	Biomarker	[9]
Myocardial infarction	DIS655KI	Strong	Biomarker	[12]
Nervous system disease	DISJ7GGT	Strong	Biomarker	[13]
Non-alcoholic fatty liver disease	DISDG1NL	Strong	Altered Expression	[14]
Obesity	DIS47Y1K	Strong	Biomarker	[15]
Obstructive sleep apnea	DIS0SVD1	Strong	Altered Expression	[16]
Prostate cancer	DISF190Y	Strong	Biomarker	[17]
Prostate neoplasm	DISHDKGQ	Strong	Biomarker	[17]
Bloom syndrome	DISKXQ7J	moderate	Altered Expression	[18]
Neuroblastoma	DISVZBI4	moderate	Biomarker	[19]
Peters anomaly	DISERK0M	moderate	Biomarker	[20]
Cataract-glaucoma syndrome	DISHZK8E	Supportive	Autosomal dominant	[21]
Early-onset posterior polar cataract	DISJFK9W	Supportive	Autosomal dominant	[22]
Intellectual disability	DISMBNXP	Disputed	Genetic Variation	[23]
Advanced cancer	DISAT1Z9	Limited	Altered Expression	[24]
Arteriosclerosis	DISK5QGC	Limited	Altered Expression	[24]
Atherosclerosis	DISMN9J3	Limited	Altered Expression	[24]
Atrial septal defect	DISJT76B	Limited	Biomarker	[25]
Autism spectrum disorder	DISXK8NV	Limited	Biomarker	[25]
Chronic obstructive pulmonary disease	DISQCIRF	Limited	Biomarker	[26]
Erectile dysfunction	DISD8MTH	Limited	Biomarker	[27]
Microphthalmia	DISGEBES	Limited	Genetic Variation	[6]
Schizophrenia	DISSRV2N	Limited	Biomarker	[13]
Young-onset Parkinson disease	DIS05LFS	Limited	Genetic Variation	[28]
------------------------------------------------------------------------------------


⏷ Show the Full List of 37 Disease(s)

Molecular Interaction Atlas (MIA)

MIA Detail

Jump to Detail Molecular Interaction Atlas of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Pituitary homeobox 3 (PITX3).	[29]
Cocaine	DMSOX7I	Approved	Cocaine decreases the expression of Pituitary homeobox 3 (PITX3).	[30]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Pituitary homeobox 3 (PITX3).	[31]
Phencyclidine	DMQBEYX	Investigative	Phencyclidine decreases the expression of Pituitary homeobox 3 (PITX3).	[34]
------------------------------------------------------------------------------------

2 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 Pituitary homeobox 3 (PITX3).	[32]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane increases the methylation of Pituitary homeobox 3 (PITX3).	[33]
------------------------------------------------------------------------------------

References

1	Recurrent 17 bp duplication in PITX3 is primarily associated with posterior polar cataract (CPP4). J Med Genet. 2004 Aug;41(8):e109. doi: 10.1136/jmg.2004.020289.
2	PITX3 mutations associated with autosomal dominant congenital cataract in the Chinese population.Mol Med Rep. 2019 Apr;19(4):3123-3131. doi: 10.3892/mmr.2019.9989. Epub 2019 Feb 26.
3	Flexible and scalable diagnostic filtering of genomic variants using G2P with Ensembl VEP. Nat Commun. 2019 May 30;10(1):2373. doi: 10.1038/s41467-019-10016-3.
4	Microphthalmia, parkinsonism, and enhanced nociception in Pitx3 ( 416insG ) mice.Mamm Genome. 2010 Feb;21(1-2):13-27. doi: 10.1007/s00335-009-9235-0. Epub 2009 Dec 22.
5	Apo E4 and lipoprotein-associated phospholipase A2 synergistically increase cardiovascular risk.Atherosclerosis. 2012 Jul;223(1):230-4. doi: 10.1016/j.atherosclerosis.2012.04.021. Epub 2012 May 8.
6	Clinical improvement of the aggressive neurobehavioral phenotype in a patient with a deletion of PITX3 and the absence of L-DOPA in the cerebrospinal fluid.Am J Med Genet B Neuropsychiatr Genet. 2012 Mar;159B(2):236-42. doi: 10.1002/ajmg.b.32020. Epub 2012 Jan 5.
7	Assessing inflammation in Chinese subjects with subtypes of heart failure: an observational study of the Chinese PLA Hospital Heart Failure Registry.J Geriatr Cardiol. 2019 Apr;16(4):313-319. doi: 10.11909/j.issn.1671-5411.2019.04.002.
8	Heterozygous and homozygous mutations in PITX3 in a large Lebanese family with posterior polar cataracts and neurodevelopmental abnormalities.Invest Ophthalmol Vis Sci. 2006 Apr;47(4):1274-80. doi: 10.1167/iovs.05-1095.
9	Inevitable isolation and the change of stress markers in hemodialysis patients during the 2015 MERS-CoV outbreak in Korea.Sci Rep. 2019 Apr 5;9(1):5676. doi: 10.1038/s41598-019-41964-x.
10	PITX3 genotype and risk of dementia in Parkinson's disease: A population-based study.J Neurol Sci. 2017 Oct 15;381:278-284. doi: 10.1016/j.jns.2017.08.3259. Epub 2017 Sep 1.
11	Pitx3 deficient mice as a genetic animal model of co-morbid depressive disorder and parkinsonism.Brain Res. 2014 Mar 13;1552:72-81. doi: 10.1016/j.brainres.2014.01.023. Epub 2014 Jan 27.
12	Pentraxin 3, ficolin-2 and lectin pathway associated serine protease MASP-3 as early predictors of myocardial infarction - the HUNT2 study.Sci Rep. 2017 Feb 20;7:43045. doi: 10.1038/srep43045.
13	From eyeless to neurological diseases.Exp Eye Res. 2017 Mar;156:5-9. doi: 10.1016/j.exer.2015.11.006. Epub 2015 Nov 22.
14	Plasma pentraxin-3 is associated with endothelial dysfunction in non-alcoholic fatty liver disease.Eur Rev Med Pharmacol Sci. 2016 Oct;20(20):4305-4312.
15	Potential prognostic biomarkers of cardiovascular disease in fetal macrosomia: the impact of gestational diabetes.J Matern Fetal Neonatal Med. 2018 Apr;31(7):895-900. doi: 10.1080/14767058.2017.1300651. Epub 2017 Mar 15.
16	Changes in inflammatory mediators as a result of intermittent hypoxia in obstructive sleep apnea syndrome.Clin Respir J. 2018 Apr;12(4):1615-1622. doi: 10.1111/crj.12718. Epub 2017 Nov 23.
17	DNA methylome changes by estradiol benzoate and bisphenol A links early-life environmental exposures to prostate cancer risk.Epigenetics. 2016 Sep;11(9):674-689. doi: 10.1080/15592294.2016.1208891. Epub 2016 Jul 14.
18	Lung inflammation after bleomycin treatment in mice: Selection of an accurate normalization strategy for gene expression analysis in an ex-vivo and in-vitro model.Int J Biochem Cell Biol. 2017 Jul;88:145-154. doi: 10.1016/j.biocel.2017.05.016. Epub 2017 May 16.
19	Pitx3 promoter directs Cre-recombinase specifically in a human neuroblastoma cell line.Mol Cell Biochem. 2008 Feb;309(1-2):223-7. doi: 10.1007/s11010-007-9655-7. Epub 2007 Nov 30.
20	Identification of PITX3 mutations in individuals with various ocular developmental defects. Ophthalmic Genet. 2018 Jun;39(3):314-320. doi: 10.1080/13816810.2018.1430243. Epub 2018 Feb 6.
21	A novel homeobox gene PITX3 is mutated in families with autosomal-dominant cataracts and ASMD. Nat Genet. 1998 Jun;19(2):167-70. doi: 10.1038/527.
22	The PITX3 gene in posterior polar congenital cataract in Australia. Mol Vis. 2006 Apr 18;12:367-71.
23	Absence of PITX3 mutation in a Tunisian family with congenital cataract and mental retardation.Mol Vis. 2010 Apr 3;16:582-5.
24	A RTK-based functional RNAi screen reveals determinants of PTX-3 expression.Int J Clin Exp Pathol. 2013;6(4):660-8. Epub 2013 Mar 15.
25	Novel and recurrent PITX3 mutations in Belgian families with autosomal dominant congenital cataract and anterior segment dysgenesis have similar phenotypic and functional characteristics.Orphanet J Rare Dis. 2014 Feb 20;9:26. doi: 10.1186/1750-1172-9-26.
26	Serum levels and gene expression of pentraxin 3 are elevated in COPD.Adv Med Sci. 2019 Mar;64(1):85-89. doi: 10.1016/j.advms.2018.08.006. Epub 2018 Dec 17.
27	Diagnostic Value of Plasma Pentraxin3- Level For Diagnosis of Erectile Dysfunction.Urol J. 2018 Jul 10;15(4):199-203. doi: 10.22037/uj.v0i0.3989.
28	PITX3 polymorphism is associated with early onset Parkinson's disease.Neurobiol Aging. 2010 Jan;31(1):114-7. doi: 10.1016/j.neurobiolaging.2008.03.008. Epub 2008 Apr 16.
29	Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
30	Transcription factors specifying dopamine phenotype are decreased in cocaine users. Neuroreport. 2004 Mar 1;15(3):401-4. doi: 10.1097/00001756-200403010-00003.
31	Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
32	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.
33	Transcriptome and DNA methylation changes modulated by sulforaphane induce cell cycle arrest, apoptosis, DNA damage, and suppression of proliferation in human liver cancer cells. Food Chem Toxicol. 2020 Feb;136:111047. doi: 10.1016/j.fct.2019.111047. Epub 2019 Dec 12.
34	Microarray Analysis of Gene Expression Alteration in Human Middle Ear Epithelial Cells Induced by Asian Sand Dust. Clin Exp Otorhinolaryngol. 2015 Dec;8(4):345-53. doi: 10.3342/ceo.2015.8.4.345. Epub 2015 Nov 10.