Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTDNS3ZQ)

• DOT Name: S-arrestin (SAG)
• Synonyms: 48 kDa protein; Retinal S-antigen; S-AG; Rod photoreceptor arrestin
• Gene Name: SAG
• Related Disease:
  Cone-rod synaptic disorder, congenital nonprogressive
  Congenital stationary night blindness 1A
  Congenital stationary night blindness 1B
  Congenital stationary night blindness 2A
  Neoplasm
  Oguchi disease-1
  Retinitis pigmentosa 47
  Bacteremia
  Behcet disease
  Cardiovascular disease
  Cleft palate
  Congenital stationary night blindness
  Cystic fibrosis
  Endometriosis
  Hepatitis C virus infection
  Hereditary hemochromatosis
  Influenza
  Isolated cleft palate
  Juvenile idiopathic arthritis
  Juvenile polyposis syndrome
  Night blindness
  Polydactyly
  Prader-Willi syndrome
  Prostate cancer
  Prostate carcinoma
  Retinitis pigmentosa 96
  Retinoblastoma
  rubella
  Uveitis
  Pharyngitis
  Oguchi disease
  Retinitis pigmentosa
  Clear cell renal carcinoma
  Kidney neoplasm
  Metastatic malignant neoplasm
  Renal cell carcinoma
  Toxic shock syndrome
  Diverticulitis
• UniProt ID: ARRS_HUMAN
• Pfam ID: PF02752 ; PF00339
• Sequence:
  MAASGKTSKSEPNHVIFKKISRDKSVTIYLGNRDYIDHVSQVQPVDGVVLVDPDLVKGKK
  VYVTLTCAFRYGQEDIDVIGLTFRRDLYFSRVQVYPPVGAASTPTKLQESLLKKLGSNTY
  PFLLTFPDYLPCSVMLQPAPQDSGKSCGVDFEVKAFATDSTDAEEDKIPKKSSVRLLIRK
  VQHAPLEMGPQPRAEAAWQFFMSDKPLHLAVSLNKEIYFHGEPIPVTVTVTNNTEKTVKK
  IKAFVEQVANVVLYSSDYYVKPVAMEEAQEKVPPNSTLTKTLTLLPLLANNRERRGIALD
  GKIKHEDTNLASSTIIKEGIDRTVLGILVSYQIKVKLTVSGFLGELTSSEVATEVPFRLM
  HPQPEDPAKESYQDANLVFEEFARHNLKDAGEAEEGKRDKNDVDE
• Function: Binds to photoactivated, phosphorylated RHO and terminates RHO signaling via G-proteins by competing with G-proteins for the same binding site on RHO. May play a role in preventing light-dependent degeneration of retinal photoreceptor cells.
• Tissue Specificity: Detected in retina, in the proximal portion of the outer segment of rod photoreceptor cells (at protein level).
• KEGG Pathway: Phototransduction (hsa04744)
• Reactome Pathway:
  Inactivation, recovery and regulation of the phototransduction cascade (R-HSA-2514859)
  Activation of the phototransduction cascade (R-HSA-2485179)

Molecular Interaction Atlas (MIA) of This DOT

38 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Cone-rod synaptic disorder, congenital nonprogressive	DIS9ZCRA	Definitive	Biomarker	[1]
Congenital stationary night blindness 1A	DISCQ9B9	Definitive	Biomarker	[1]
Congenital stationary night blindness 1B	DISZ8V5R	Definitive	Biomarker	[1]
Congenital stationary night blindness 2A	DISA57KI	Definitive	Biomarker	[1]
Neoplasm	DISZKGEW	Definitive	Altered Expression	[2]
Oguchi disease-1	DIS3QMBO	Definitive	Autosomal recessive	[1]
Retinitis pigmentosa 47	DISV5QG1	Definitive	Autosomal dominant	[3]
Bacteremia	DIS6N9RZ	Strong	Genetic Variation	[4]
Behcet disease	DISSYMBS	Strong	Altered Expression	[5]
Cardiovascular disease	DIS2IQDX	Strong	Genetic Variation	[6]
Cleft palate	DIS6G5TF	Strong	Biomarker	[7]
Congenital stationary night blindness	DISX0CWK	Strong	Genetic Variation	[8]
Cystic fibrosis	DIS2OK1Q	Strong	Genetic Variation	[9]
Endometriosis	DISX1AG8	Strong	Biomarker	[10]
Hepatitis C virus infection	DISQ0M8R	Strong	Biomarker	[11]
Hereditary hemochromatosis	DISVG5MT	Strong	Genetic Variation	[12]
Influenza	DIS3PNU3	Strong	Biomarker	[13]
Isolated cleft palate	DISV80CD	Strong	Biomarker	[7]
Juvenile idiopathic arthritis	DISQZGBV	Strong	Biomarker	[14]
Juvenile polyposis syndrome	DISBPSLH	Strong	Genetic Variation	[15]
Night blindness	DIS335K9	Strong	Genetic Variation	[16]
Polydactyly	DIS25BMZ	Strong	Biomarker	[17]
Prader-Willi syndrome	DISYWMLU	Strong	Altered Expression	[18]
Prostate cancer	DISF190Y	Strong	Biomarker	[19]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[19]
Retinitis pigmentosa 96	DIS77RNC	Strong	Autosomal dominant	[20]
Retinoblastoma	DISVPNPB	Strong	Biomarker	[21]
rubella	DISXUI9P	Strong	Biomarker	[22]
Uveitis	DISV0RYS	Strong	Biomarker	[23]
Pharyngitis	DISSN548	moderate	Genetic Variation	[24]
Oguchi disease	DISLYKY5	Supportive	Autosomal recessive	[25]
Retinitis pigmentosa	DISCGPY8	Supportive	Autosomal dominant	[26]
Clear cell renal carcinoma	DISBXRFJ	Disputed	Altered Expression	[27]
Kidney neoplasm	DISBNZTN	Disputed	Altered Expression	[27]
Metastatic malignant neoplasm	DIS86UK6	Disputed	Altered Expression	[27]
Renal cell carcinoma	DISQZ2X8	Disputed	Altered Expression	[27]
Toxic shock syndrome	DISX5S53	Disputed	Biomarker	[28]
Diverticulitis	DIS1AK7Q	Limited	Biomarker	[29]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of S-arrestin (SAG).	[30]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of S-arrestin (SAG).	[31]

References

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• [2] Validation of SAG/RBX2/ROC2 E3 ubiquitin ligase as an anticancer and radiosensitizing target.Clin Cancer Res. 2010 Feb 1;16(3):814-24. doi: 10.1158/1078-0432.CCR-09-1592. Epub 2010 Jan 26.
• [3] A Novel Dominant Mutation in SAG, the Arrestin-1 Gene, Is a Common Cause of Retinitis Pigmentosa in Hispanic Families in the Southwestern United States. Invest Ophthalmol Vis Sci. 2017 May 1;58(5):2774-2784. doi: 10.1167/iovs.16-21341.
• [4] Lack of correlation of virulence gene profiles of Staphylococcus aureus bacteremia isolates with mortality.Microb Pathog. 2019 Aug;133:103543. doi: 10.1016/j.micpath.2019.103543. Epub 2019 May 15.
• [5] S-antigen specific T helper type 1 response is present in Behcet's disease.Mol Vis. 2008 Aug 7;14:1456-64.
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• [7] Perturbed development of cranial neural crest cells in association with reduced sonic hedgehog signaling underlies the pathogenesis of retinoic-acid-induced cleft palate.Dis Model Mech. 2019 Oct 4;12(10):dmm040279. doi: 10.1242/dmm.040279.
• [8] Genotyping microarray for CSNB-associated genes.Invest Ophthalmol Vis Sci. 2009 Dec;50(12):5919-26. doi: 10.1167/iovs.09-3548. Epub 2009 Jul 2.
• [9] Superantigen types in Staphylococcus aureus isolated from patients with cystic fibrosis.Folia Microbiol (Praha). 2006;51(6):614-8. doi: 10.1007/BF02931628.
• [10] Autoreactive epitopes within the human alpha-enolase and their recognition by sera from patients with endometriosis.J Autoimmun. 1995 Dec;8(6):931-45. doi: 10.1016/s0896-8411(95)80027-1.
• [11] Up-regulation of Hedgehog pathway is associated with cellular permissiveness for hepatitis C virus replication.Hepatology. 2011 Nov;54(5):1580-90. doi: 10.1002/hep.24576.
• [12] Molecular mechanisms of Ellisvan Creveld gene variations in ventricular septal defect.Mol Med Rep. 2018 Jan;17(1):1527-1536. doi: 10.3892/mmr.2017.8088. Epub 2017 Nov 15.
• [13] Investigation of the potential of a 48 kDa protein as a vaccine candidate for infection against nontypable Haemophilus influenzae.Vaccine. 2007 May 16;25(20):4012-9. doi: 10.1016/j.vaccine.2007.02.048. Epub 2007 Mar 8.
• [14] Cellular immune responses of patients with juvenile chronic arthritis to retinal antigens and their synthetic peptides.Immunol Res. 1996;15(1):74-83. doi: 10.1007/BF02918285.
• [15] Superantigens in Staphylococcus aureus isolated from prosthetic joint infection.Diagn Microbiol Infect Dis. 2015 Mar;81(3):201-7. doi: 10.1016/j.diagmicrobio.2014.11.007. Epub 2014 Nov 24.
• [16] Arrestin mutations: Some cause diseases, others promise cure.Prog Mol Biol Transl Sci. 2019;161:29-45. doi: 10.1016/bs.pmbts.2018.09.004. Epub 2018 Oct 24.
• [17] Preaxial polydactyly following early gestational exposure to the smoothened agonist, SAG, in C57BL/6J mice.Birth Defects Res. 2017 Jan 20;109(1):49-54. doi: 10.1002/bdra.23571.
• [18] Whole genome microarray analysis of gene expression in Prader-Willi syndrome.Am J Med Genet A. 2007 Mar 1;143A(5):430-42. doi: 10.1002/ajmg.a.31606.
• [19] Paracrine sonic hedgehog signaling contributes significantly to acquired steroidogenesis in the prostate tumor microenvironment.Int J Cancer. 2017 Jan 15;140(2):358-369. doi: 10.1002/ijc.30450. Epub 2016 Oct 20.
• [20] The rabbit as an animal model to study pharmacokinetics of norethindrone in women. Contraception. 1979 Dec;20(6):619-32. doi: 10.1016/s0010-7824(79)80040-2.
• [21] Identification of differentially expressed proteins in retinoblastoma tumors using mass spectrometry-based comparative proteomic approach.J Proteomics. 2017 Apr 21;159:77-91. doi: 10.1016/j.jprot.2017.02.006. Epub 2017 Feb 13.
• [22] Preliminary multiplex microarray IgG immunoassay for the diagnosis of toxoplasmosis and rubella.Mem Inst Oswaldo Cruz. 2017 Jun;112(6):428-436. doi: 10.1590/0074-02760160509.
• [23] Effect of deferoxamine on retinal lipid peroxidation in experimental uveitis.Invest Ophthalmol Vis Sci. 1993 Oct;34(11):3084-9.
• [24] Molecular analysis of Streptococcus pyogenes strains isolated from Chinese children with pharyngitis.Diagn Microbiol Infect Dis. 2011 Feb;69(2):117-22. doi: 10.1016/j.diagmicrobio.2010.09.011.
• [25] Gene analysis and evaluation of the single founder effect in Japanese patients with Oguchi disease. Jpn J Ophthalmol. 2004 Jul-Aug;48(4):350-2. doi: 10.1007/s10384-004-0070-2.
• [26] 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.
• [27] Autoantibody against arrestin-1 as a potential biomarker of renal cell carcinoma.Biochimie. 2019 Feb;157:26-37. doi: 10.1016/j.biochi.2018.10.019. Epub 2018 Oct 30.
• [28] Staphylococcus aureus express unique superantigens depending on the tissue source.J Infect Dis. 2003 Jan 1;187(1):77-86. doi: 10.1086/345874. Epub 2002 Dec 13.
• [29] Randomised clinical trial: mesalazine versus placebo in the prevention of diverticulitis recurrence.Aliment Pharmacol Ther. 2017 Aug;46(3):282-291. doi: 10.1111/apt.14152. Epub 2017 May 23.
• [30] 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.
• [31] Benzo[a]pyrene-induced changes in microRNA-mRNA networks. Chem Res Toxicol. 2012 Apr 16;25(4):838-49.