Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTK050I3)

• DOT Name: Protein XRP2 (RP2)
• Gene Name: RP2
• Related Disease:
  Disorder of orbital region
  Inherited retinal dystrophy
  Retinitis pigmentosa 2
  RP2-related retinopathy
  Congenital stationary night blindness 2A
  Leber hereditary optic neuropathy
  Myopia
  Night blindness
  Polycystic ovarian syndrome
  Retinitis pigmentosa
• UniProt ID: XRP2_HUMAN
• PDB ID: 2BX6; 3BH6; 3BH7
• Pfam ID: PF07986
• Sequence:
  MGCFFSKRRKADKESRPENEEERPKQYSWDQREKVDPKDYMFSGLKDETVGRLPGTVAGQ
  QFLIQDCENCNIYIFDHSATVTIDDCTNCIIFLGPVKGSVFFRNCRDCKCTLACQQFRVR
  DCRKLEVFLCCATQPIIESSSNIKFGCFQWYYPELAFQFKDAGLSIFNNTWSNIHDFTPV
  SGELNWSLLPEDAVVQDYVPIPTTEELKAVRVSTEANRSIVPISRGQRQKSSDESCLVVL
  FAGDYTIANARKLIDEMVGKGFFLVQTKEVSMKAEDAQRVFREKAPDFLPLLNKGPVIAL
  EFNGDGAVEVCQLIVNEIFNGTKMFVSESKETASGDVDSFYNFADIQMGI
• Function: Acts as a GTPase-activating protein (GAP) involved in trafficking between the Golgi and the ciliary membrane. Involved in localization of proteins, such as NPHP3, to the cilium membrane by inducing hydrolysis of GTP ARL3, leading to the release of UNC119 (or UNC119B). Acts as a GTPase-activating protein (GAP) for tubulin in concert with tubulin-specific chaperone C, but does not enhance tubulin heterodimerization. Acts as a guanine nucleotide dissociation inhibitor towards ADP-ribosylation factor-like proteins.
• Tissue Specificity: Ubiquitous. Expressed in the rod and cone photoreceptors, extending from the tips of the outer segment (OS) through the inner segment (IS) and outer nuclear layer (ONL) and into the synaptic terminals of the outer plexiform layer (ONL). Also detected in the bipolar, horizontal and amacrine cells in the inner nuclear layer (INL), extending to the inner plexiform layer (IPL) and though the ganglion cell layer (GCL) and into the nerve fiber layer (NFL) (at protein level).
• Reactome Pathway: Trafficking of myristoylated proteins to the cilium (R-HSA-5624138)

Molecular Interaction Atlas (MIA) of This DOT

10 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Disorder of orbital region	DISH0ECJ	Definitive	Biomarker	[1]
Inherited retinal dystrophy	DISGGL77	Definitive	Genetic Variation	[2]
Retinitis pigmentosa 2	DISLBNCM	Definitive	X-linked	[3]
RP2-related retinopathy	DISSUKEW	Definitive	X-linked	[4]
Congenital stationary night blindness 2A	DISA57KI	Strong	Genetic Variation	[5]
Leber hereditary optic neuropathy	DIS7Y2EE	Strong	Genetic Variation	[6]
Myopia	DISK5S60	Strong	Genetic Variation	[7]
Night blindness	DIS335K9	Strong	Genetic Variation	[7]
Polycystic ovarian syndrome	DISZ2BNG	Strong	Biomarker	[8]
Retinitis pigmentosa	DISCGPY8	Supportive	Autosomal dominant	[9]

10 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 Protein XRP2 (RP2).	[10]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Protein XRP2 (RP2).	[11]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Protein XRP2 (RP2).	[12]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Protein XRP2 (RP2).	[13]
Ivermectin	DMDBX5F	Approved	Ivermectin increases the expression of Protein XRP2 (RP2).	[14]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide decreases the expression of Protein XRP2 (RP2).	[15]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Protein XRP2 (RP2).	[16]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Protein XRP2 (RP2).	[17]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of Protein XRP2 (RP2).	[19]
Milchsaure	DM462BT	Investigative	Milchsaure affects the expression of Protein XRP2 (RP2).	[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 increases the methylation of Protein XRP2 (RP2).	[18]

References

• [1] Functional analysis of retinitis pigmentosa 2 (RP2) protein reveals variable pathogenic potential of disease-associated missense variants.PLoS One. 2011;6(6):e21379. doi: 10.1371/journal.pone.0021379. Epub 2011 Jun 27.
• [2] X-linked retinitis pigmentosa: RPGR mutations in most families with definite X linkage and clustering of mutations in a short sequence stretch of exon ORF15.Invest Ophthalmol Vis Sci. 2003 Apr;44(4):1458-63. doi: 10.1167/iovs.02-0605.
• [3] Protein-truncation mutations in the RP2 gene in a North American cohort of families with X-linked retinitis pigmentosa. Am J Hum Genet. 1999 Mar;64(3):897-900. doi: 10.1086/302298.
• [4] 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.
• [5] Localization of CSNBX (CSNB4) between the retinitis pigmentosa loci RP2 and RP3 on proximal Xp.Invest Ophthalmol Vis Sci. 1997 Dec;38(13):2750-5.
• [6] Novel mutation in RP2 gene in two brothers with X-linked retinitis pigmentosa and mtDNA mutation of leber hereditary optic neuropathy who showed marked differences in clinical severity.Am J Ophthalmol. 2000 Sep;130(3):357-9. doi: 10.1016/s0002-9394(00)00553-5.
• [7] Phenotype-genotype correlations in X linked retinitis pigmentosa.J Med Genet. 1992 Sep;29(9):615-23. doi: 10.1136/jmg.29.9.615.
• [8] Progesterone resistance in PCOS endometrium: a microarray analysis in clomiphene citrate-treated and artificial menstrual cycles.J Clin Endocrinol Metab. 2011 Jun;96(6):1737-46. doi: 10.1210/jc.2010-2600. Epub 2011 Mar 16.
• [9] 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.
• [10] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [11] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [12] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [13] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [14] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [15] Oxidative stress modulates theophylline effects on steroid responsiveness. Biochem Biophys Res Commun. 2008 Dec 19;377(3):797-802.
• [16] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [17] The contribution of methotrexate exposure and host factors on transcriptional variance in human liver. Toxicol Sci. 2007 Jun;97(2):582-94.
• [18] 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.
• [19] A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.
• [20] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.