Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT0NBPL5)

• DOT Name: Protein eyes shut homolog (EYS)
• Synonyms: Epidermal growth factor-like protein 10; EGF-like protein 10; Epidermal growth factor-like protein 11; EGF-like protein 11; Protein spacemaker homolog
• Gene Name: EYS
• Related Disease:
  EYS-related retinopathy
  Inherited retinal dystrophy
  Retinitis pigmentosa 25
  Adrenogenital syndrome
  Alpha-1 antitrypsin deficiency
  Cone-rod dystrophy
  Cone-rod dystrophy 2
  Congenital adrenal hyperplasia
  Major depressive disorder
  Mood disorder
  Myopathy
  Night blindness
  Retinopathy
  Schizophrenia
  Alcohol dependence
  Congenital muscular dystrophy
  Duodenal ulcer
  Hereditary macular dystrophy
  Retinitis pigmentosa
  Age-related macular degeneration
• UniProt ID: EYS_HUMAN
• Pfam ID: PF00008 ; PF12661 ; PF02210
• Sequence:
  MTDKSIVILSLMVFHSSFINGKTCRRQLVEEWHPQPSSYVVNWTLTENICLDFYRDCWFL
  GVNTKIDTSGNQAVPQICPLQIQLGDILVISSEPSLQFPEINLMNVSETSFVGCVQNTTT
  EDQLLFGCRLKGMHTVNSKWLSVGTHYFITVMASGPSPCPLGLRLNVTVKQQFCQESLSS
  EFCSGHGKCLSEAWSKTYSCHCQPPFSGKYCQELDACSFKPCKNNGSCINKRENWDEQAY
  ECVCHPPFTGKNCSEIIGQCQPHVCFHGNCSNITSNSFICECDEQFSGPFCEVSAKPCVS
  LLFWKRGICPNSSSAYTYECPKGSSSQNGETDVSEFSLVPCQNGTDCIKISNDVMCICSP
  IFTDLLCKSIQTSCESFPLRNNATCKKCEKDYPCSCISGFTEKNCEKAIDHCKLLSINCL
  NEEWCFNIIGRFKYVCIPGCTKNPCWFLKNVYLIHQHLCYCGVTFHGICQDKGPAQFEYV
  WQLGFAGSEGEKCQGVIDAYFFLAANCTEDATYVNDPEDNNSSCWFPHEGTKEICANGCS
  CLSEEDSQEYRYLCFLRWAGNMYLENTTDDQENECQHEAVCKDEINRPRCSCSLSYIGRL
  CVVNVDYCLGNHSISVHGLCLALSHNCNCSGLQRYERNICEIDTEDCKSASCKNGTTSTH
  LRGYFFRKCVPGFKGTQCEIDIDECASHPCKNGATCIDQPGNYFCQCVPPFKVVDGFSCL
  CNPGYVGIRCEQDIDDCILNACEHNSTCKDLHLSYQCVCLSDWEGNFCEQESNECKMNPC
  KNNSTCTDLYKSYRCECTSGWTGQNCSEEINECDSDPCMNGGLCHESTIPGQFVCLCPPL
  YTGQFCHQRYNLCDLLHNPCRNNSTCLALVDANQHCICREEFEGKNCEIDVKDCLFLSCQ
  DYGDCEDMVNNFRCICRPGFSGSLCEIEINECSSEPCKNNGTCVDLTNRFFCNCEPEYHG
  PFCELDVNKCKISPCLDEENCVYRTDGYNCLCAPGYTGINCEINLDECLSEPCLHDGVCI
  DGINHYTCDCKSGFFGTHCETNANDCLSNPCLHGRCTELINEYPCSCDADGTSTQCKIKI
  NDCTSIPCMNEGFCQKSAHGFTCICPRGYTGAYCEKSIDNCAEPELNSVICLNGGICVDG
  PGHTFDCRCLPGFSGQFCEININECSSSPCLHGADCEDHINGYVCKCQPGWSGHHCENEL
  ECIPNSCVHELCMENEPGSTCLCTPGFMTCSIGLLCGDEIRRITCLTPIFQRTDPISTQT
  YTIPPSETLVSSFPSIKATRIPAIMDTYPVDQGPKQTGIVKHDILPTTGLATLRISTPLE
  SYLLQELIVTRELSAKHSLLSSADVSSSRFLNFGIRDPAQIVQDKTSVSHMPIRTSAATL
  GFFFPDRRARTPFIMSSLMSDFIFPTQSLLFENCQTVALSATPTTSVIRSIPGADIELNR
  QSLLSRGFLLIAASISATPVVSRGAQEDIEEYSADSLISRREHWRLLSPSMSPIFPAKVI
  ISKQVTILNSSALHRFSTKAFNPSEYQAITEASSNQRLTNIKSQAADSLRELSQTCATCS
  MTEIKSSREFSDQVLHSKQSHFYETFWMNSAILASWYALMGAQTITSGHSFSSATEITPS
  VAFTEVPSLFPSKKSAKRTILSSSLEESITLSSNLDVNLCLDKTCLSIVPSQTISSDLMN
  SDLTSKMTTDELSVSENILKLLKIRQYGITMGPTEVLNQESLLDMEKSKGSHTLFKLHPS
  DSSLDFELNLQIYPDVTLKTYSEITHANDFKNNLPPLTGSVPDFSEVTTNVAFYTVSATP
  ALSIQTSSSMSVIRPDWPYFTDYMTSLKKEVKTSSEWSKWELQPSVQYQEFPTASRHLPF
  TRSLTLSSLESILAPQRLMISDFSCVRYYGDSYLEFQNVALNPQNNISLEFQTFSSYGLL
  LYVKQDSNLVDGFFIQLFIENGTLKYHFYCPGEAKFKSINTTVRVDNGQKYTLLIRQELD
  PCNAELTILGRNTQICESINHVLGKPLPKSGSVFIGGFPDLHGKIQMPVPVKNFTGCIEV
  IEINNWRSFIPSKAVKNYHINNCRSQGFMLSPTASFVDASDVTQGVDTMWTSVSPSVAAP
  SVCQQDVCHNGGTCHAIFLSSGIVSFQCDCPLHFTGRFCEKDAGLFFPSFNGNSYLELPF
  LKFVLEKEHNRTVTIYLTIKTNSLNGTILYSNGNNCGKQFLHLFLVEGRPSVKYGCGNSQ
  NILTVSANYSINTNAFTPITIRYTTPVGSPGVVCMIEMTADGKPPVQKKDTEISHASQAY
  FESMFLGHIPANVQIHKKAGPVYGFRGCILDLQVNNKEFFIIDEARHGKNIENCHVPWCA
  HHLCRNNGTCISDNENLFCECPRLYSGKLCQFASCENNPCGNGATCVPKSGTDIVCLCPY
  GRSGPLCTDAINITQPRFSGTDAFGYTSFLAYSRISDISFHYEFHLKFQLANNHSALQNN
  LIFFTGQKGHGLNGDDFLAVGLLNGSVVYSYNLGSGIASIRSEPLNLSLGVHTVHLGKFF
  QEGWLKVDDHKNKSIIAPGRLVGLNVFSQFYVGGYSEYTPDLLPNGADFKNGFQGCIFTL
  QVRTEKDGHFRGLGNPEGHPNAGRSVGQCHASPCSLMKCGNGGTCIESGTSVYCNCTTGW
  KGSFCTETVSTCDPEHDPPHHCSRGATCISLPHGYTCFCPLGTTGIYCEQALILIVILEK
  PKPAERKVKKEALSISDPSFRSNELSWMSFASFHVRKKTHIQLQFQPLAADGILFYAAQH
  LKAQSGDFLCISLVNSSVQLRYNLGDRTIILETLQKVTINGSTWHIIKAGRVGAEGYLDL
  DGINVTEKASTKMSSLDTNTDFYIGGVSSLNLVNPMAIENEPVGFQGCIRQVIINNQELQ
  LTEFGAKGGSNVGDCDGTACGYNTCRNGGECTVNGTTFSCRCLPDWAGNTCNQSVSCLNN
  LCLHQSLCIPDQSFSYSCLCTLGWVGRYCENKTSFSTAKFMGNSYIKYIDPNYRMRNLQF
  TTISLNFSTTKTEGLIVWMGIAQNEENDFLAIGLHNQTLKIAVNLGERISVPMSYNNGTF
  CCNKWHHVVVIQNQTLIKAYINNSLILSEDIDPHKNFVALNYDGICYLGGFEYGRKVNIV
  TQEIFKTNFVGKIKDVVFFQEPKNIELIKLEGYNVYDGDEQNEVT
• Function: Required to maintain the integrity of photoreceptor cells. Specifically required for normal morphology of the photoreceptor ciliary pocket, and might thus facilitate protein trafficking between the photoreceptor inner and outer segments via the transition zone.
• Tissue Specificity: Expressed in retina (at protein level) . Isoform 1: Detected in retina . Isoform 2: Detected in retina . Isoform 3: Strongly expressed in retina and testis . Isoform 4: Strongly expressed in testis, and weakly expressed in retina .

Molecular Interaction Atlas (MIA) of This DOT

20 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
EYS-related retinopathy	DISRKR4Z	Definitive	Autosomal recessive	[1]
Inherited retinal dystrophy	DISGGL77	Definitive	CausalMutation	[2]
Retinitis pigmentosa 25	DISTIKZB	Definitive	Autosomal recessive	[3]
Adrenogenital syndrome	DIS2N76U	Strong	Genetic Variation	[4]
Alpha-1 antitrypsin deficiency	DISQKEHW	Strong	Genetic Variation	[4]
Cone-rod dystrophy	DISY9RWN	Strong	Genetic Variation	[5]
Cone-rod dystrophy 2	DISX2RWY	Strong	Genetic Variation	[5]
Congenital adrenal hyperplasia	DISG873W	Strong	Genetic Variation	[4]
Major depressive disorder	DIS4CL3X	Strong	Genetic Variation	[6]
Mood disorder	DISLVMWO	Strong	Genetic Variation	[7]
Myopathy	DISOWG27	Strong	Genetic Variation	[8]
Night blindness	DIS335K9	Strong	Genetic Variation	[9]
Retinopathy	DISB4B0F	Strong	Biomarker	[5]
Schizophrenia	DISSRV2N	Strong	Genetic Variation	[10]
Alcohol dependence	DIS4ZSCO	moderate	Genetic Variation	[11]
Congenital muscular dystrophy	DISKY7OY	moderate	Biomarker	[12]
Duodenal ulcer	DISNHHCN	moderate	Genetic Variation	[13]
Hereditary macular dystrophy	DISEYSYY	moderate	Genetic Variation	[5]
Retinitis pigmentosa	DISCGPY8	Supportive	Autosomal dominant	[14]
Age-related macular degeneration	DIS0XS2C	Limited	Genetic Variation	[5]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Protein eyes shut homolog (EYS).	[15]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Protein eyes shut homolog (EYS).	[16]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Protein eyes shut homolog (EYS).	[17]

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] Whole Genome Sequencing Increases Molecular Diagnostic Yield Compared with Current Diagnostic Testing for Inherited Retinal Disease.Ophthalmology. 2016 May;123(5):1143-50. doi: 10.1016/j.ophtha.2016.01.009. Epub 2016 Feb 9.
• [3] The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources. Genet Med. 2022 Aug;24(8):1732-1742. doi: 10.1016/j.gim.2022.04.017. Epub 2022 May 4.
• [4] Exome-based search for recurrent disease-causing alleles in Russian population.Eur J Med Genet. 2019 Jul;62(7):103656. doi: 10.1016/j.ejmg.2019.04.013. Epub 2019 Apr 24.
• [5] Extending the Spectrum of EYS-Associated Retinal Disease to Macular Dystrophy.Invest Ophthalmol Vis Sci. 2019 May 1;60(6):2049-2063. doi: 10.1167/iovs.18-25531.
• [6] Genome-wide interaction study of a proxy for stress-sensitivity and its prediction of major depressive disorder.PLoS One. 2018 Dec 20;13(12):e0209160. doi: 10.1371/journal.pone.0209160. eCollection 2018.
• [7] Meta-analysis of genome-wide association studies for neuroticism in 449,484 individuals identifies novel genetic loci and pathways.Nat Genet. 2018 Jul;50(7):920-927. doi: 10.1038/s41588-018-0151-7. Epub 2018 Jun 25.
• [8] Association of common variants in the human eyes shut ortholog (EYS) with statin-induced myopathy: evidence for additional functions of EYS.Muscle Nerve. 2011 Oct;44(4):531-8. doi: 10.1002/mus.22115. Epub 2011 Aug 8.
• [9] Mutations in the EYS gene account for approximately 5% of autosomal recessive retinitis pigmentosa and cause a fairly homogeneous phenotype.Ophthalmology. 2010 Oct;117(10):2026-33, 2033.e1-7. doi: 10.1016/j.ophtha.2010.01.040.
• [10] Genome-Wide Association Study Detected Novel Susceptibility Genes for Schizophrenia and Shared Trans-Populations/Diseases Genetic Effect.Schizophr Bull. 2019 Jun 18;45(4):824-834. doi: 10.1093/schbul/sby140.
• [11] Common PTP4A1-PHF3-EYS variants are specific for alcohol dependence.Am J Addict. 2014 Jul-Aug;23(4):411-4. doi: 10.1111/j.1521-0391.2013.12115.x. Epub 2013 Sep 13.
• [12] Large copy-number variations in patients with statin-associated myopathy affecting statin myopathy-related loci.Physiol Res. 2016 Dec 13;65(6):1005-1011. doi: 10.33549/physiolres.933284. Epub 2016 Aug 19.
• [13] A genome-wide association study identifies two susceptibility loci for duodenal ulcer in the Japanese population.Nat Genet. 2012 Mar 4;44(4):430-4, S1-2. doi: 10.1038/ng.1109.
• [14] 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.
• [15] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [16] 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.
• [17] 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.