Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTJ7O69I)

• DOT Name: X-linked retinitis pigmentosa GTPase regulator (RPGR)
• Gene Name: RPGR
• Related Disease:
  Retinitis pigmentosa 3
  RPGR-related retinopathy
  Obsolete primary ciliary dyskinesia-retinitis pigmentosa syndrome
  Cone-rod dystrophy
  Primary ciliary dyskinesia
  Retinitis pigmentosa
  Macular degeneration, X-linked atrophic
• UniProt ID: RPGR_HUMAN
• PDB ID: 4JHN; 4JHP; 4QAM
• Pfam ID: PF00415
• Sequence:
  MREPEELMPDSGAVFTFGKSKFAENNPGKFWFKNDVPVHLSCGDEHSAVVTGNNKLYMFG
  SNNWGQLGLGSKSAISKPTCVKALKPEKVKLAACGRNHTLVSTEGGNVYATGGNNEGQLG
  LGDTEERNTFHVISFFTSEHKIKQLSAGSNTSAALTEDGRLFMWGDNSEGQIGLKNVSNV
  CVPQQVTIGKPVSWISCGYYHSAFVTTDGELYVFGEPENGKLGLPNQLLGNHRTPQLVSE
  IPEKVIQVACGGEHTVVLTENAVYTFGLGQFGQLGLGTFLFETSEPKVIENIRDQTISYI
  SCGENHTALITDIGLMYTFGDGRHGKLGLGLENFTNHFIPTLCSNFLRFIVKLVACGGCH
  MVVFAAPHRGVAKEIEFDEINDTCLSVATFLPYSSLTSGNVLQRTLSARMRRRERERSPD
  SFSMRRTLPPIEGTLGLSACFLPNSVFPRCSERNLQESVLSEQDLMQPEEPDYLLDEMTK
  EAEIDNSSTVESLGETTDILNMTHIMSLNSNEKSLKLSPVQKQKKQQTIGELTQDTALTE
  NDDSDEYEEMSEMKEGKACKQHVSQGIFMTQPATTIEAFSDEEVGNDTGQVGPQADTDGE
  GLQKEVYRHENNNGVDQLDAKEIEKESDGGHSQKESEAEEIDSEKETKLAEIAGMKDLRE
  REKSTKKMSPFFGNLPDRGMNTESEENKDFVKKRESCKQDVIFDSERESVEKPDSYMEGA
  SESQQGIADGFQQPEAIEFSSGEKEDDEVETDQNIRYGRKLIEQGNEKETKPIISKSMAK
  YDFKCDRLSEIPEEKEGAEDSKGNGIEEQEVEANEENVKVHGGRKEKTEILSDDLTDKAE
  DHEFSKTEELKLEDVDEEINAENVESKKKTVGDDESVPTGYHSKTEGAERTNDDSSAETI
  EKKEKANLEERAICEYNENPKGYMLDDADSSSLEILENSETTPSKDMKKTKKIFLFKRVP
  SINQKIVKNNNEPLPEIKSIGDQIILKSDNKDADQNHMSQNHQNIPPTNTERRSKSCTIL
• Function: Could be a guanine-nucleotide releasing factor. Plays a role in ciliogenesis. Probably regulates cilia formation by regulating actin stress filaments and cell contractility. Plays an important role in photoreceptor integrity. May play a critical role in spermatogenesis and in intraflagellar transport processes. May be involved in microtubule organization and regulation of transport in primary cilia.
• Tissue Specificity: Heart, brain, placenta, lung, liver, muscle, kidney, retina, pancreas and fetal retinal pigment epithelium. Isoform 3 is found only in the retina. Colocalizes with RPGRIP1 in the outer segment of rod photoreceptors and cone outer segments.

Molecular Interaction Atlas (MIA) of This DOT

7 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Retinitis pigmentosa 3	DIS4VBK1	Definitive	X-linked	[1]
RPGR-related retinopathy	DISRRD6A	Definitive	X-linked	[2]
Obsolete primary ciliary dyskinesia-retinitis pigmentosa syndrome	DISI0OIU	Strong	X-linked	[3]
Cone-rod dystrophy	DISY9RWN	Supportive	Autosomal dominant	[4]
Primary ciliary dyskinesia	DISOBC7V	Supportive	Autosomal dominant	[5]
Retinitis pigmentosa	DISCGPY8	Supportive	Autosomal dominant	[5]
Macular degeneration, X-linked atrophic	DISL84CF	Limited	X-linked	[6]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of X-linked retinitis pigmentosa GTPase regulator (RPGR).	[7]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of X-linked retinitis pigmentosa GTPase regulator (RPGR).	[8]
Estradiol	DMUNTE3	Approved	Estradiol affects the expression of X-linked retinitis pigmentosa GTPase regulator (RPGR).	[9]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of X-linked retinitis pigmentosa GTPase regulator (RPGR).	[10]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of X-linked retinitis pigmentosa GTPase regulator (RPGR).	[11]
Menadione	DMSJDTY	Approved	Menadione affects the expression of X-linked retinitis pigmentosa GTPase regulator (RPGR).	[11]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of X-linked retinitis pigmentosa GTPase regulator (RPGR).	[13]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of X-linked retinitis pigmentosa GTPase regulator (RPGR).	[14]
2-AMINO-1-METHYL-6-PHENYLIMIDAZO[4,5-B]PYRIDINE	DMNQL17	Investigative	2-AMINO-1-METHYL-6-PHENYLIMIDAZO[4,5-B]PYRIDINE decreases the expression of X-linked retinitis pigmentosa GTPase regulator (RPGR).	[16]

3 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 increases the methylation of X-linked retinitis pigmentosa GTPase regulator (RPGR).	[12]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of X-linked retinitis pigmentosa GTPase regulator (RPGR).	[15]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of X-linked retinitis pigmentosa GTPase regulator (RPGR).	[15]

References

• [1] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [2] 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.
• [3] RPGR mutation associated with retinitis pigmentosa, impaired hearing, and sinorespiratory infections. J Med Genet. 2003 Aug;40(8):609-15. doi: 10.1136/jmg.40.8.609.
• [4] X-linked cone-rod dystrophy (locus COD1): identification of mutations in RPGR exon ORF15. Am J Hum Genet. 2002 Apr;70(4):1049-53. doi: 10.1086/339620. Epub 2002 Feb 20.
• [5] Clinical Practice Guidelines for Rare Diseases: The Orphanet Database. PLoS One. 2017 Jan 18;12(1):e0170365. doi: 10.1371/journal.pone.0170365. eCollection 2017.
• [6] X-linked recessive atrophic macular degeneration from RPGR mutation. Genomics. 2002 Aug;80(2):166-71. doi: 10.1006/geno.2002.6815.
• [7] 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.
• [8] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [9] Identification of novel low-dose bisphenol a targets in human foreskin fibroblast cells derived from hypospadias patients. PLoS One. 2012;7(5):e36711. doi: 10.1371/journal.pone.0036711. Epub 2012 May 4.
• [10] Systems analysis of transcriptome and proteome in retinoic acid/arsenic trioxide-induced cell differentiation/apoptosis of promyelocytic leukemia. Proc Natl Acad Sci U S A. 2005 May 24;102(21):7653-8.
• [11] Time series analysis of oxidative stress response patterns in HepG2: a toxicogenomics approach. Toxicology. 2013 Apr 5;306:24-34.
• [12] 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.
• [13] Targeting MYCN in neuroblastoma by BET bromodomain inhibition. Cancer Discov. 2013 Mar;3(3):308-23.
• [14] 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.
• [15] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [16] 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.