Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTHU807A)

DOT Name Eyes absent homolog 1 (EYA1)
Synonyms EC 3.1.3.16; EC 3.1.3.48
Gene Name EYA1
Related Disease
Branchio-oto-renal syndrome ( )
Branchiootorenal syndrome 1 ( )
Chronic kidney disease ( )
Nephropathy ( )
Anxiety ( )
Anxiety disorder ( )
Autism spectrum disorder ( )
Branchiootic syndrome 1 ( )
Branchiootorenal syndrome 2 ( )
Breast neoplasm ( )
Bronchiolitis obliterans syndrome ( )
Cockayne syndrome ( )
Colorectal carcinoma ( )
Colorectal neoplasm ( )
Cowden disease ( )
Deafness ( )
Depression ( )
DiGeorge syndrome ( )
Ear malformation ( )
Focal segmental glomerulosclerosis ( )
Gastric cancer ( )
Hydrocephalus ( )
Hypospadias ( )
Kidney failure ( )
Medulloblastoma ( )
Multicystic dysplastic kidney ( )
Neoplasm ( )
Otofaciocervical syndrome ( )
Renal dysplasia ( )
Shprintzen-Goldberg syndrome ( )
Stomach cancer ( )
Trichohepatoenteric syndrome ( )
Vesicoureteral reflux ( )
Branchiootic syndrome ( )
Advanced cancer ( )
Branchiooculofacial syndrome ( )
Childhood kidney Wilms tumor ( )
Hepatocellular carcinoma ( )
Melanoma ( )
Metastatic malignant neoplasm ( )
Metastatic melanoma ( )
Otofaciocervical syndrome 1 ( )
Wilms tumor ( )
UniProt ID
EYA1_HUMAN
3D Structure
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2D Sequence (FASTA)
Download
3D Structure (PDB)
Download
EC Number
3.1.3.16; 3.1.3.48
Pfam ID
PF00702
Sequence
MEMQDLTSPHSRLSGSSESPSGPKLGNSHINSNSMTPNGTEVKTEPMSSSETASTTADGS
LNNFSGSAIGSSSFSPRPTHQFSPPQIYPSNRPYPHILPTPSSQTMAAYGQTQFTTGMQQ
ATAYATYPQPGQPYGISSYGALWAGIKTEGGLSQSQSPGQTGFLSYGTSFSTPQPGQAPY
SYQMQGSSFTTSSGIYTGNNSLTNSSGFNSSQQDYPSYPSFGQGQYAQYYNSSPYPAHYM
TSSNTSPTTPSTNATYQLQEPPSGITSQAVTDPTAEYSTIHSPSTPIKDSDSDRLRRGSD
GKSRGRGRRNNNPSPPPDSDLERVFIWDLDETIIVFHSLLTGSYANRYGRDPPTSVSLGL
RMEEMIFNLADTHLFFNDLEECDQVHIDDVSSDDNGQDLSTYNFGTDGFPAAATSANLCL
ATGVRGGVDWMRKLAFRYRRVKEIYNTYKNNVGGLLGPAKREAWLQLRAEIEALTDSWLT
LALKALSLIHSRTNCVNILVTTTQLIPALAKVLLYGLGIVFPIENIYSATKIGKESCFER
IIQRFGRKVVYVVIGDGVEEEQGAKKHAMPFWRISSHSDLMALHHALELEYL
Function
Functions both as protein phosphatase and as transcriptional coactivator for SIX1, and probably also for SIX2, SIX4 and SIX5. Tyrosine phosphatase that dephosphorylates 'Tyr-142' of histone H2AX (H2AXY142ph) and promotes efficient DNA repair via the recruitment of DNA repair complexes containing MDC1. 'Tyr-142' phosphorylation of histone H2AX plays a central role in DNA repair and acts as a mark that distinguishes between apoptotic and repair responses to genotoxic stress. Its function as histone phosphatase may contribute to its function in transcription regulation during organogenesis. Has also phosphatase activity with proteins phosphorylated on Ser and Thr residues (in vitro). Required for normal embryonic development of the craniofacial and trunk skeleton, kidneys and ears. Together with SIX1, it plays an important role in hypaxial muscle development; in this it is functionally redundant with EYA2.
Tissue Specificity
In the embryo, highly expressed in kidney with lower levels in brain. Weakly expressed in lung. In the adult, highly expressed in heart and skeletal muscle. Weakly expressed in brain and liver. No expression in eye or kidney.
KEGG Pathway
Transcriptio.l misregulation in cancer (hsa05202 )
Reactome Pathway
Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks (R-HSA-5693565 )

Molecular Interaction Atlas (MIA) of This DOT

43 Disease(s) Related to This DOT
Disease Name Disease ID Evidence Level Mode of Inheritance REF
Branchio-oto-renal syndrome DISIPQ53 Definitive Autosomal dominant [1]
Branchiootorenal syndrome 1 DISXDFVU Definitive Autosomal dominant [2]
Chronic kidney disease DISW82R7 Definitive Genetic Variation [3]
Nephropathy DISXWP4P Definitive Genetic Variation [4]
Anxiety DISIJDBA Strong Genetic Variation [5]
Anxiety disorder DISBI2BT Strong Genetic Variation [5]
Autism spectrum disorder DISXK8NV Strong Biomarker [6]
Branchiootic syndrome 1 DISZ5BR7 Strong Autosomal dominant [7]
Branchiootorenal syndrome 2 DISEB137 Strong Biomarker [8]
Breast neoplasm DISNGJLM Strong Biomarker [9]
Bronchiolitis obliterans syndrome DISCK9IV Strong Genetic Variation [10]
Cockayne syndrome DISW6GL2 Strong Genetic Variation [11]
Colorectal carcinoma DIS5PYL0 Strong Biomarker [12]
Colorectal neoplasm DISR1UCN Strong Altered Expression [12]
Cowden disease DISMYKCE Strong Biomarker [13]
Deafness DISKCLH4 Strong Biomarker [14]
Depression DIS3XJ69 Strong Genetic Variation [5]
DiGeorge syndrome DIST1RKO Strong Genetic Variation [15]
Ear malformation DISVJGPS Strong Biomarker [16]
Focal segmental glomerulosclerosis DISJNHH0 Strong Genetic Variation [17]
Gastric cancer DISXGOUK Strong Biomarker [18]
Hydrocephalus DISIZUF7 Strong Genetic Variation [19]
Hypospadias DIS48CCP Strong Genetic Variation [15]
Kidney failure DISOVQ9P Strong Genetic Variation [20]
Medulloblastoma DISZD2ZL Strong Biomarker [21]
Multicystic dysplastic kidney DISJ9R1F Strong CausalMutation [22]
Neoplasm DISZKGEW Strong Biomarker [23]
Otofaciocervical syndrome DISLYABR Strong GermlineCausalMutation [24]
Renal dysplasia DIS3DFGD Strong Genetic Variation [25]
Shprintzen-Goldberg syndrome DISQH6P3 Strong Genetic Variation [26]
Stomach cancer DISKIJSX Strong Biomarker [18]
Trichohepatoenteric syndrome DISL3ODF Strong Genetic Variation [27]
Vesicoureteral reflux DISUL6SA Strong CausalMutation [22]
Branchiootic syndrome DIS3X164 Supportive Autosomal dominant [28]
Advanced cancer DISAT1Z9 Limited Genetic Variation [6]
Branchiooculofacial syndrome DISHJ9O9 Limited Biomarker [8]
Childhood kidney Wilms tumor DIS0NMK3 Limited Altered Expression [29]
Hepatocellular carcinoma DIS0J828 Limited Biomarker [30]
Melanoma DIS1RRCY Limited Altered Expression [31]
Metastatic malignant neoplasm DIS86UK6 Limited Biomarker [32]
Metastatic melanoma DISSL43L Limited Altered Expression [31]
Otofaciocervical syndrome 1 DISZJB3G Limited Autosomal dominant [24]
Wilms tumor DISB6T16 Limited Altered Expression [29]
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⏷ Show the Full List of 43 Disease(s)
Molecular Interaction Atlas (MIA) Jump to Detail Molecular Interaction Atlas of This DOT
18 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 Eyes absent homolog 1 (EYA1). [33]
Tretinoin DM49DUI Approved Tretinoin decreases the expression of Eyes absent homolog 1 (EYA1). [34]
Acetaminophen DMUIE76 Approved Acetaminophen decreases the expression of Eyes absent homolog 1 (EYA1). [35]
Doxorubicin DMVP5YE Approved Doxorubicin decreases the expression of Eyes absent homolog 1 (EYA1). [36]
Carbamazepine DMZOLBI Approved Carbamazepine affects the expression of Eyes absent homolog 1 (EYA1). [37]
Isotretinoin DM4QTBN Approved Isotretinoin decreases the expression of Eyes absent homolog 1 (EYA1). [33]
Azacitidine DMTA5OE Approved Azacitidine decreases the expression of Eyes absent homolog 1 (EYA1). [39]
Cocaine DMSOX7I Approved Cocaine increases the expression of Eyes absent homolog 1 (EYA1). [40]
Thalidomide DM70BU5 Approved Thalidomide decreases the expression of Eyes absent homolog 1 (EYA1). [33]
Phenytoin DMNOKBV Approved Phenytoin decreases the expression of Eyes absent homolog 1 (EYA1). [33]
Nilotinib DM7HXWT Approved Nilotinib decreases the expression of Eyes absent homolog 1 (EYA1). [33]
Abacavir DMMN36E Approved Abacavir decreases the expression of Eyes absent homolog 1 (EYA1). [33]
Polyethylene glycol DM4I1JP Approved Polyethylene glycol decreases the expression of Eyes absent homolog 1 (EYA1). [33]
Dabigatran DMDI6R4 Approved Dabigatran decreases the expression of Eyes absent homolog 1 (EYA1). [33]
Ramelteon DM7IW9J Approved Ramelteon decreases the expression of Eyes absent homolog 1 (EYA1). [33]
PMID28460551-Compound-2 DM4DOUB Patented PMID28460551-Compound-2 decreases the expression of Eyes absent homolog 1 (EYA1). [42]
PMID28870136-Compound-52 DMFDERP Patented PMID28870136-Compound-52 decreases the expression of Eyes absent homolog 1 (EYA1). [33]
Trichostatin A DM9C8NX Investigative Trichostatin A increases the expression of Eyes absent homolog 1 (EYA1). [43]
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⏷ Show the Full List of 18 Drug(s)
2 Drug(s) Affected the Post-Translational Modifications of This DOT
Drug Name Drug ID Highest Status Interaction REF
Fulvestrant DM0YZC6 Approved Fulvestrant decreases the methylation of Eyes absent homolog 1 (EYA1). [38]
Benzo(a)pyrene DMN7J43 Phase 1 Benzo(a)pyrene increases the methylation of Eyes absent homolog 1 (EYA1). [41]
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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 Clustering of mutations responsible for branchio-oto-renal (BOR) syndrome in the eyes absent homologous region (eyaHR) of EYA1. Hum Mol Genet. 1997 Dec;6(13):2247-55. doi: 10.1093/hmg/6.13.2247.
3 Genome-wide association study for renal traits in the Framingham Heart and Atherosclerosis Risk in Communities Studies.BMC Med Genet. 2008 Jun 3;9:49. doi: 10.1186/1471-2350-9-49.
4 Phenotypic consequences in a Japanese family having branchio-oto-renal syndrome with a novel frameshift mutation in the gene EYA1.Acta Otolaryngol. 2007 Jan;127(1):98-104. doi: 10.1080/00016480500527185.
5 Genome-wide analyses of borderline personality features.Mol Psychiatry. 2014 Aug;19(8):923-9. doi: 10.1038/mp.2013.109. Epub 2013 Aug 27.
6 Alteration of gut microbiota-associated epitopes in children with autism spectrum disorders.Brain Behav Immun. 2019 Jan;75:192-199. doi: 10.1016/j.bbi.2018.10.006. Epub 2018 Oct 27.
7 PanelApp crowdsources expert knowledge to establish consensus diagnostic gene panels. Nat Genet. 2019 Nov;51(11):1560-1565. doi: 10.1038/s41588-019-0528-2.
8 Thymus, kidney and craniofacial abnormalities in Six 1 deficient mice.Mech Dev. 2003 Jun;120(6):669-79. doi: 10.1016/s0925-4773(03)00065-0.
9 EYA1 phosphatase function is essential to drive breast cancer cell proliferation through cyclin D1.Cancer Res. 2013 Jul 15;73(14):4488-99. doi: 10.1158/0008-5472.CAN-12-4078. Epub 2013 May 1.
10 Whole exome sequencing identifies a mutation in EYA1 and GLI3 in a patient with branchiootic syndrome and esophageal atresia: Coincidence or a digenic mode of inheritance?.Mol Med Rep. 2018 Feb;17(2):3200-3205. doi: 10.3892/mmr.2017.8196. Epub 2017 Dec 6.
11 Abnormal sensitivity of some Cockayne's syndrome cell strains to UV- and gamma-rays. Association with a reduced ability to repair potentially lethal damage.Mutat Res. 1984 Feb;131(2):61-70. doi: 10.1016/0167-8817(84)90012-9.
12 EYA1 promotes tumor angiogenesis by activating the PI3K pathway in colorectal cancer.Exp Cell Res. 2018 Jun 1;367(1):37-46. doi: 10.1016/j.yexcr.2018.02.028. Epub 2018 Feb 27.
13 Eya1 and Eya2 gene expression is down-regulated during somitic myogenesis in the cadmium-induced omphalocele chick model.J Pediatr Surg. 2012 Jun;47(6):1123-7. doi: 10.1016/j.jpedsurg.2012.03.014.
14 Identification of three novel mutations in human EYA1 protein associated with branchio-oto-renal syndrome.Hum Mutat. 1998;11(6):443-9. doi: 10.1002/(SICI)1098-1004(1998)11:6<443::AID-HUMU4>3.0.CO;2-S.
15 Six1 and Eya1 are critical regulators of peri-cloacal mesenchymal progenitors during genitourinary tract development.Dev Biol. 2011 Dec 1;360(1):186-94. doi: 10.1016/j.ydbio.2011.09.020. Epub 2011 Sep 24.
16 Identification of a novel nonsynonymous mutation of EYA1 disrupting splice site in a Korean patient with BOR syndrome.Mol Biol Rep. 2014 Jul;41(7):4321-7. doi: 10.1007/s11033-014-3303-6. Epub 2014 Mar 4.
17 Branchio-Oto-Renal Syndrome (BOR) associated with focal glomerulosclerosis in a patient with a novel EYA1 splice site mutation.BMC Nephrol. 2013 Mar 18;14:60. doi: 10.1186/1471-2369-14-60.
18 EYA1 expression in gastric carcinoma and its association with clinicopathological characteristics: a pilot study.Med Oncol. 2014 May;31(5):955. doi: 10.1007/s12032-014-0955-y. Epub 2014 Apr 12.
19 A proposed new contiguous gene syndrome on 8q consists of Branchio-Oto-Renal (BOR) syndrome, Duane syndrome, a dominant form of hydrocephalus and trapeze aplasia; implications for the mapping of the BOR gene.Hum Mol Genet. 1994 Oct;3(10):1859-66. doi: 10.1093/hmg/3.10.1859.
20 Clinically diverse phenotypes and genotypes of patients with branchio-oto-renal syndrome.J Hum Genet. 2018 May;63(5):647-656. doi: 10.1038/s10038-018-0429-8. Epub 2018 Mar 2.
21 The Eya1 phosphatase promotes Shh signaling during hindbrain development and oncogenesis.Dev Cell. 2015 Apr 6;33(1):22-35. doi: 10.1016/j.devcel.2015.01.033. Epub 2015 Mar 26.
22 Whole-exome sequencing in the molecular diagnosis of individuals with congenital anomalies of the kidney and urinary tract and identification of a new causative gene.Genet Med. 2017 Apr;19(4):412-420. doi: 10.1038/gim.2016.131. Epub 2016 Sep 22.
23 A Sialylated-Bortezomib Prodrug Strategy Based on a Highly Expressed Selectin Target for the Treatment of Leukemia or Solid Tumors.Pharm Res. 2019 Nov 4;36(12):176. doi: 10.1007/s11095-019-2714-4.
24 Point mutation of an EYA1-gene splice site in a patient with oto-facio-cervical syndrome. Ann Hum Genet. 2006 Jan;70(Pt 1):140-4. doi: 10.1111/j.1529-8817.2005.00204.x.
25 The earpits-deafness syndrome. Clinical and genetic aspects.Int J Pediatr Otorhinolaryngol. 1980 Nov;2(4):309-22. doi: 10.1016/0165-5876(80)90036-1.
26 EYA1 mutation in a newborn female presenting with cardiofacial syndrome.Pediatr Cardiol. 2004 Jul-Aug;25(4):411-3. doi: 10.1007/s00246-003-0271-3.
27 Identification of a novel mutation in the EYA1 gene in a Korean family with branchio-oto-renal (BOR) syndrome.Int J Pediatr Otorhinolaryngol. 2005 Aug;69(8):1123-8. doi: 10.1016/j.ijporl.2005.03.003. Epub 2005 Apr 8.
28 BOR and BO syndromes are allelic defects of EYA1. Eur J Hum Genet. 1997 Jul-Aug;5(4):242-6.
29 Loss of heterozygosity at 2q37 in sporadic Wilms' tumor: putative role for miR-562.Clin Cancer Res. 2009 Oct 1;15(19):5985-92. doi: 10.1158/1078-0432.CCR-09-1065. Epub 2009 Sep 29.
30 LINC00511 as a ceRNA promotes cell malignant behaviors and correlates with prognosis of hepatocellular carcinoma patients by modulating miR-195/EYA1 axis.Biomed Pharmacother. 2020 Jan;121:109642. doi: 10.1016/j.biopha.2019.109642. Epub 2019 Nov 12.
31 Eyes absent gene (EYA1) is a pathogenic driver and a therapeutic target for melanoma.Oncotarget. 2017 Sep 27;8(62):105081-105092. doi: 10.18632/oncotarget.21352. eCollection 2017 Dec 1.
32 EYA1 promotes cell migration and tumor metastasis in hepatocellular carcinoma.Am J Transl Res. 2019 Apr 15;11(4):2328-2338. eCollection 2019.
33 Exposure-based assessment of chemical teratogenicity using morphogenetic aggregates of human embryonic stem cells. Reprod Toxicol. 2020 Jan;91:74-91. doi: 10.1016/j.reprotox.2019.10.004. Epub 2019 Nov 8.
34 Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
35 Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
36 Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
37 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.
38 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.
39 The effect of DNA methylation inhibitor 5-Aza-2'-deoxycytidine on human endometrial stromal cells. Hum Reprod. 2010 Nov;25(11):2859-69.
40 Gene expression profile of the nucleus accumbens of human cocaine abusers: evidence for dysregulation of myelin. J Neurochem. 2004 Mar;88(5):1211-9. doi: 10.1046/j.1471-4159.2003.02247.x.
41 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.
42 Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
43 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.