Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT4VBD78)

• DOT Name: Aryl-hydrocarbon-interacting protein-like 1 (AIPL1)
• Gene Name: AIPL1
• Related Disease:
  AIPL1-related retinopathy
  Leber congenital amaurosis 4
  Blindness
  Cone dystrophy
  Cone-rod dystrophy 2
  Disorder of orbital region
  Inherited retinal dystrophy
  Keratoconus
  Leber congenital amaurosis 1
  Leber hereditary optic neuropathy
  Retinitis pigmentosa
  Retinoblastoma
  Cone-rod dystrophy
  Leber congenital amaurosis
  Cataract
  Late-onset retinal degeneration
  Microphthalmia
  Mitochondrial encephalomyopathy
  Neuroblastoma
  Retinopathy
• UniProt ID: AIPL1_HUMAN
• PDB ID: 5U9A; 5U9I; 5U9J; 5U9K; 5V35; 6PX0
• Sequence:
  MDAALLLNVEGVKKTILHGGTGELPNFITGSRVIFHFRTMKCDEERTVIDDSRQVGQPMH
  IIIGNMFKLEVWEILLTSMRVHEVAEFWCDTIHTGVYPILSRSLRQMAQGKDPTEWHVHT
  CGLANMFAYHTLGYEDLDELQKEPQPLVFVIELLQVDAPSDYQRETWNLSNHEKMKAVPV
  LHGEGNRLFKLGRYEEASSKYQEAIICLRNLQTKEKPWEVQWLKLEKMINTLILNYCQCL
  LKKEEYYEVLEHTSDILRHHPGIVKAYYVRARAHAEVWNEAEAKADLQKVLELEPSMQKA
  VRRELRLLENRMAEKQEEERLRCRNMLSQGATQPPAEPPTEPPAQSSTEPPAEPPTAPSA
  ELSAGPPAEPATEPPPSPGHSLQH
• Function: May be important in protein trafficking and/or protein folding and stabilization.
• Tissue Specificity: Highly expressed in retina. Specifically localized to the developing photoreceptor layer and within the photoreceptors of the adult retina.
• KEGG Pathway:
  Cushing syndrome (hsa04934)
  Chemical carcinogenesis - receptor activation (hsa05207)

Molecular Interaction Atlas (MIA) of This DOT

20 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
AIPL1-related retinopathy	DIS0O22O	Definitive	Autosomal recessive	[1]
Leber congenital amaurosis 4	DISOWA5A	Definitive	Autosomal recessive	[2]
Blindness	DISTIM10	Strong	Genetic Variation	[3]
Cone dystrophy	DIS7SAZZ	Strong	Genetic Variation	[4]
Cone-rod dystrophy 2	DISX2RWY	Strong	Altered Expression	[5]
Disorder of orbital region	DISH0ECJ	Strong	Biomarker	[6]
Inherited retinal dystrophy	DISGGL77	Strong	Genetic Variation	[7]
Keratoconus	DISOONXH	Strong	Biomarker	[8]
Leber congenital amaurosis 1	DISY2B33	Strong	Genetic Variation	[9]
Leber hereditary optic neuropathy	DIS7Y2EE	Strong	Genetic Variation	[10]
Retinitis pigmentosa	DISCGPY8	Strong	Genetic Variation	[11]
Retinoblastoma	DISVPNPB	Strong	Biomarker	[12]
Cone-rod dystrophy	DISY9RWN	moderate	Biomarker	[5]
Leber congenital amaurosis	DISMGH8F	Supportive	Autosomal dominant	[13]
Cataract	DISUD7SL	Limited	Genetic Variation	[14]
Late-onset retinal degeneration	DIST9GP4	Limited	Genetic Variation	[15]
Microphthalmia	DISGEBES	Limited	Genetic Variation	[6]
Mitochondrial encephalomyopathy	DISA6PTN	Limited	Biomarker	[15]
Neuroblastoma	DISVZBI4	Limited	Biomarker	[16]
Retinopathy	DISB4B0F	Limited	Genetic Variation	[9]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Brilinta	DMBR01X	Approved	Aryl-hydrocarbon-interacting protein-like 1 (AIPL1) increases the Peripheral sensory neuropathy ADR of Brilinta.	[21]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Cisplatin	DMRHGI9	Approved	Cisplatin affects the expression of Aryl-hydrocarbon-interacting protein-like 1 (AIPL1).	[17]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Aryl-hydrocarbon-interacting protein-like 1 (AIPL1).	[18]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of Aryl-hydrocarbon-interacting protein-like 1 (AIPL1).	[17]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of Aryl-hydrocarbon-interacting protein-like 1 (AIPL1).	[20]

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 Aryl-hydrocarbon-interacting protein-like 1 (AIPL1).	[19]

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] Prevalence of AIPL1 mutations in inherited retinal degenerative disease. Mol Genet Metab. 2000 Jun;70(2):142-50. doi: 10.1006/mgme.2000.3001.
• [3] Interaction of the tetratricopeptide repeat domain of aryl hydrocarbon receptor-interacting protein-like 1 with the regulatory P subunit of phosphodiesterase 6.J Biol Chem. 2019 Oct 25;294(43):15795-15807. doi: 10.1074/jbc.RA119.010666. Epub 2019 Sep 5.
• [4] AIPL1, A protein linked to blindness, is essential for the stability of enzymes mediating cGMP metabolism in cone photoreceptor cells.Hum Mol Genet. 2014 Feb 15;23(4):1002-12. doi: 10.1093/hmg/ddt496. Epub 2013 Oct 9.
• [5] Viral-mediated vision rescue of a novel AIPL1 cone-rod dystrophy model.Hum Mol Genet. 2015 Feb 1;24(3):670-84. doi: 10.1093/hmg/ddu487. Epub 2014 Sep 30.
• [6] Genome-wide homozygosity mapping in families with leber congenital amaurosis identifies mutations in AIPL1 and RDH12 genes.DNA Cell Biol. 2014 Dec;33(12):876-83. doi: 10.1089/dna.2014.2554.
• [7] Gene therapy for retinitis pigmentosa and Leber congenital amaurosis caused by defects in AIPL1: effective rescue of mouse models of partial and complete Aipl1 deficiency using AAV2/2 and AAV2/8 vectors.Hum Mol Genet. 2009 Jun 15;18(12):2099-114. doi: 10.1093/hmg/ddp133. Epub 2009 Mar 19.
• [8] Leber Congenital Amaurosis.Adv Exp Med Biol. 2018;1085:131-137. doi: 10.1007/978-3-319-95046-4_26.
• [9] The Leber Congenital Amaurosis-Linked Protein AIPL1 and Its Critical Role in Photoreceptors.Adv Exp Med Biol. 2018;1074:381-386. doi: 10.1007/978-3-319-75402-4_47.
• [10] The Leber congenital amaurosis protein AIPL1 modulates the nuclear translocation of NUB1 and suppresses inclusion formation by NUB1 fragments.J Biol Chem. 2004 Nov 12;279(46):48038-47. doi: 10.1074/jbc.M407871200. Epub 2004 Aug 30.
• [11] Gene therapy with a promoter targeting both rods and cones rescues retinal degeneration caused by AIPL1 mutations.Gene Ther. 2010 Jan;17(1):117-31. doi: 10.1038/gt.2009.104. Epub 2009 Aug 27.
• [12] The Leber congenital amaurosis gene product AIPL1 is localized exclusively in rod photoreceptors of the adult human retina.Hum Mol Genet. 2002 Apr 1;11(7):823-31. doi: 10.1093/hmg/11.7.823.
• [13] Review and update on the molecular basis of Leber congenital amaurosis. World J Clin Cases. 2015 Feb 16;3(2):112-24. doi: 10.12998/wjcc.v3.i2.112.
• [14] The phenotype of Leber congenital amaurosis in patients with AIPL1 mutations.Arch Ophthalmol. 2004 Jul;122(7):1029-37. doi: 10.1001/archopht.122.7.1029.
• [15] Histopathologic-genotypic correlations in retinitis pigmentosa and allied diseases.Ophthalmic Genet. 2005 Jun;26(2):91-100. doi: 10.1080/13816810590968032.
• [16] The Leber congenital amaurosis protein AIPL1 and EB proteins co-localize at the photoreceptor cilium.PLoS One. 2015 Mar 23;10(3):e0121440. doi: 10.1371/journal.pone.0121440. eCollection 2015.
• [17] Acute hypersensitivity of pluripotent testicular cancer-derived embryonal carcinoma to low-dose 5-aza deoxycytidine is associated with global DNA Damage-associated p53 activation, anti-pluripotency and DNA demethylation. PLoS One. 2012;7(12):e53003. doi: 10.1371/journal.pone.0053003. Epub 2012 Dec 27.
• [18] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [19] 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.
• [20] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [21] Pharmacoethnicity in Paclitaxel-Induced Sensory Peripheral Neuropathy. Clin Cancer Res. 2015 Oct 1;21(19):4337-46. doi: 10.1158/1078-0432.CCR-15-0133. Epub 2015 May 26.