Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTABESO9)

• DOT Name: X-linked retinitis pigmentosa GTPase regulator-interacting protein 1 (RPGRIP1)
• Synonyms: RPGR-interacting protein 1
• Gene Name: RPGRIP1
• Related Disease:
  Cone-rod dystrophy 13
  Leber congenital amaurosis 6
  Eye disorder
  Joubert syndrome
  Leber hereditary optic neuropathy
  Nephronophthisis
  Obesity
  Retinitis pigmentosa
  Retinopathy
  Vascular dementia
  Inherited retinal dystrophy
  Pathologic nystagmus
  Cone-rod dystrophy
  Leber congenital amaurosis
  Leber congenital amaurosis 1
  Ciliopathy
  Cone-rod dystrophy 2
  Glaucoma/ocular hypertension
  Meckel syndrome, type 1
  OPTN-related open angle glaucoma
• UniProt ID: RPGR1_HUMAN
• PDB ID: 4QAM
• Pfam ID: PF00168 ; PF11618 ; PF18111
• Sequence:
  MSHLVDPTSGDLPVRDIDAIPLVLPASKGKNMKTQPPLSRMNREELEDSFFRLREDHMLV
  KELSWKQQDEIKRLRTTLLRLTAAGRDLRVAEEAAPLSETARRGQKAGWRQRLSMHQRPQ
  MHRLQGHFHCVGPASPRRAQPRVQVGHRQLHTAGAPVPEKPKRGPRDRLSYTAPPSFKEH
  ATNENRGEVASKPSELVSGSNSIISFSSVISMAKPIGLCMPNSAHIMASNTMQVEEPPKS
  PEKMWPKDENFEQRSSLECAQKAAELRASIKEKVELIRLKKLLHERNASLVMTKAQLTEV
  QEAYETLLQKNQGILSAAHEALLKQVNELRAELKEESKKAVSLKSQLEDVSILQMTLKEF
  QERVEDLEKERKLLNDNYDKLLESMLDSSDSSSQPHWSNELIAEQLQQQVSQLQDQLDAE
  LEDKRKVLLELSREKAQNEDLKLEVTNILQKHKQEVELLQNAATISQPPDRQSEPATHPA
  VLQENTQIEPSEPKNQEEKKLSQVLNELQVSHAETTLELEKTRDMLILQRKINVCYQEEL
  EAMMTKADNDNRDHKEKLERLTRLLDLKNNRIKQLEGILRSHDLPTSEQLKDVAYGTRPL
  SLCLETLPAHGDEDKVDISLLHQGENLFELHIHQAFLTSAALAQAGDTQPTTFCTYSFYD
  FETHCTPLSVGPQPLYDFTSQYVMETDSLFLHYLQEASARLDIHQAMASEHSTLAAGWIC
  FDRVLETVEKVHGLATLIGAGGEEFGVLEYWMRLRFPIKPSLQACNKRKKAQVYLSTDVL
  GGRKAQEEEFRSESWEPQNELWIEITKCCGLRSRWLGTQPSPYAVYRFFTFSDHDTAIIP
  ASNNPYFRDQARFPVLVTSDLDHYLRREALSIHVFDDEDLEPGSYLGRARVPLLPLAKNE
  SIKGDFNLTDPAEKPNGSIQVQLDWKFPYIPPESFLKPEAQTKGKDTKDSSKISSEEEKA
  SFPSQDQMASPEVPIEAGQYRSKRKPPHGGERKEKEHQVVSYSRRKHGKRIGVQGKNRME
  YLSLNILNGNTPEQVNYTEWKFSETNSFIGDGFKNQHEEEEMTLSHSALKQKEPLHPVND
  KESSEQGSEVSEAQTTDSDDVIVPPMSQKYPKADSEKMCIEIVSLAFYPEAEVMSDENIK
  QVYVEYKFYDLPLSETETPVSLRKPRAGEEIHFHFSKVIDLDPQEQQGRRRFLFDMLNGQ
  DPDQGHLKFTVVSDPLDEEKKECEEVGYAYLQLWQILESGRDILEQELDIVSPEDLATPI
  GRLKVSLQAAAVLHAIYKEMTEDLFS
• Function: May function as scaffolding protein. Required for normal location of RPGR at the connecting cilium of photoreceptor cells. Required for normal disk morphogenesis and disk organization in the outer segment of photoreceptor cells and for survival of photoreceptor cells.
• Tissue Specificity: Strong expression in retina, with weaker expression in testis. Expressed in other neurons such as amacrine cells. Colocalizes with RGPR in the outer segment of rod photoreceptors and cone outer segments.

Molecular Interaction Atlas (MIA) of This DOT

20 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Cone-rod dystrophy 13	DIS2EXT7	Definitive	Autosomal recessive	[1]
Leber congenital amaurosis 6	DISRS4F2	Definitive	Autosomal recessive	[2]
Eye disorder	DISB52BH	Strong	Genetic Variation	[3]
Joubert syndrome	DIS7P5CO	Strong	Genetic Variation	[4]
Leber hereditary optic neuropathy	DIS7Y2EE	Strong	Genetic Variation	[5]
Nephronophthisis	DISXU4HY	Strong	Biomarker	[6]
Obesity	DIS47Y1K	Strong	Biomarker	[7]
Retinitis pigmentosa	DISCGPY8	Strong	Genetic Variation	[8]
Retinopathy	DISB4B0F	Strong	Biomarker	[9]
Vascular dementia	DISVO82H	Strong	Genetic Variation	[10]
Inherited retinal dystrophy	DISGGL77	moderate	Genetic Variation	[11]
Pathologic nystagmus	DIS1QSPO	moderate	Genetic Variation	[2]
Cone-rod dystrophy	DISY9RWN	Supportive	Autosomal dominant	[1]
Leber congenital amaurosis	DISMGH8F	Supportive	Autosomal dominant	[12]
Leber congenital amaurosis 1	DISY2B33	Disputed	Genetic Variation	[13]
Ciliopathy	DIS10G4I	Limited	Genetic Variation	[5]
Cone-rod dystrophy 2	DISX2RWY	Limited	Biomarker	[14]
Glaucoma/ocular hypertension	DISLBXBY	Limited	Genetic Variation	[15]
Meckel syndrome, type 1	DIS4YWZU	Limited	Genetic Variation	[5]
OPTN-related open angle glaucoma	DISDR98A	Limited	Genetic Variation	[15]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of X-linked retinitis pigmentosa GTPase regulator-interacting protein 1 (RPGRIP1).	[16]
2-AMINO-1-METHYL-6-PHENYLIMIDAZO[4,5-B]PYRIDINE	DMNQL17	Investigative	2-AMINO-1-METHYL-6-PHENYLIMIDAZO[4,5-B]PYRIDINE increases the expression of X-linked retinitis pigmentosa GTPase regulator-interacting protein 1 (RPGRIP1).	[18]

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 decreases the methylation of X-linked retinitis pigmentosa GTPase regulator-interacting protein 1 (RPGRIP1).	[17]

References

• [1] Evidence of RPGRIP1 gene mutations associated with recessive cone-rod dystrophy. J Med Genet. 2003 Aug;40(8):616-9. doi: 10.1136/jmg.40.8.616.
• [2] Null RPGRIP1 alleles in patients with Leber congenital amaurosis. Am J Hum Genet. 2001 May;68(5):1295-8. doi: 10.1086/320113. Epub 2001 Mar 29.
• [3] A post-hoc comparison of the utility of sanger sequencing and exome sequencing for the diagnosis of heterogeneous diseases.Hum Mutat. 2013 Dec;34(12):1721-6. doi: 10.1002/humu.22450. Epub 2013 Oct 18.
• [4] A common allele in RPGRIP1L is a modifier of retinal degeneration in ciliopathies.Nat Genet. 2009 Jun;41(6):739-45. doi: 10.1038/ng.366. Epub 2009 May 10.
• [5] The ciliopathy-associated protein homologs RPGRIP1 and RPGRIP1L are linked to cilium integrity through interaction with Nek4 serine/threonine kinase.Hum Mol Genet. 2011 Sep 15;20(18):3592-605. doi: 10.1093/hmg/ddr280. Epub 2011 Jun 17.
• [6] Interaction of nephrocystin-4 and RPGRIP1 is disrupted by nephronophthisis or Leber congenital amaurosis-associated mutations.Proc Natl Acad Sci U S A. 2005 Dec 20;102(51):18520-5. doi: 10.1073/pnas.0505774102. Epub 2005 Dec 9.
• [7] Association of fat mass and obesity-associated and retinitis pigmentosa guanosine triphosphatase (GTPase) regulator-interacting protein-1 like polymorphisms with body mass index in Chinese women.Endocr J. 2018 Jul 28;65(7):783-791. doi: 10.1507/endocrj.EJ17-0554. Epub 2018 Apr 14.
• [8] Rpgrip1 is required for rod outer segment development and ciliary protein trafficking in zebrafish.Sci Rep. 2017 Dec 4;7(1):16881. doi: 10.1038/s41598-017-12838-x.
• [9] Limited proteolysis differentially modulates the stability and subcellular localization of domains of RPGRIP1 that are distinctly affected by mutations in Leber's congenital amaurosis.Hum Mol Genet. 2005 May 15;14(10):1327-40. doi: 10.1093/hmg/ddi143. Epub 2005 Mar 30.
• [10] Genetic association of the gene encoding RPGRIP1L with susceptibility to vascular dementia.Gene. 2012 May 10;499(1):160-2. doi: 10.1016/j.gene.2012.03.010. Epub 2012 Mar 8.
• [11] Canine RPGRIP1 mutation establishes cone-rod dystrophy in miniature longhaired dachshunds as a homologue of human Leber congenital amaurosis.Genomics. 2006 Sep;88(3):293-301. doi: 10.1016/j.ygeno.2006.05.004. Epub 2006 Jun 27.
• [12] Complete exon-intron structure of the RPGR-interacting protein (RPGRIP1) gene allows the identification of mutations underlying Leber congenital amaurosis. Eur J Hum Genet. 2001 Aug;9(8):561-71. doi: 10.1038/sj.ejhg.5200689.
• [13] Identification of a novel RPGRIP1 mutation in an Iranian family with leber congenital amaurosis by exome sequencing.J Cell Mol Med. 2018 Mar;22(3):1733-1742. doi: 10.1111/jcmm.13454. Epub 2017 Nov 29.
• [14] Author Correction: Variabilities in retinal function and structure in a canine model of cone-rod dystrophy associated with RPGRIP1 support multigenic etiology.Sci Rep. 2018 Aug 24;8(1):13058. doi: 10.1038/s41598-018-31337-1.
• [15] Evidence for RPGRIP1 gene as risk factor for primary open angle glaucoma.Eur J Hum Genet. 2011 Apr;19(4):445-51. doi: 10.1038/ejhg.2010.217. Epub 2011 Jan 12.
• [16] Retinoic acid receptor alpha amplifications and retinoic acid sensitivity in breast cancers. Clin Breast Cancer. 2013 Oct;13(5):401-8.
• [17] 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.
• [18] Preferential induction of the AhR gene battery in HepaRG cells after a single or repeated exposure to heterocyclic aromatic amines. Toxicol Appl Pharmacol. 2010 Nov 15;249(1):91-100.