Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT2L9Y6M)

• DOT Name: Protein RD3 (RD3)
• Synonyms: Retinal degeneration protein 3
• Gene Name: RD3
• Related Disease:
  Leber congenital amaurosis 12
  Retinopathy
  Blindness
  Gonorrhea
  Leber congenital amaurosis 1
  Neoplasm
  Neuroblastoma
  Retinitis pigmentosa
  Leber congenital amaurosis
• UniProt ID: RD3_HUMAN
• PDB ID: 6DRF
• Pfam ID: PF14473
• Sequence:
  MSLISWLRWNEAPSRLSTRSPAEMVLETLMMELTGQMREAERQQRERSNAVRKVCTGVDY
  SWLASTPRSTYDLSPIERLQLEDVCVKIHPSYCGPAILRFRQLLAEQEPEVQEVSQLFRS
  VLQEVLERMKQEEEAHKLTRQWSLRPRGSLATFKTRARISPFASDIRTISEDVERDTPPP
  LRSWSMPEFRAPKAD
• Function: Plays a critical role in the regulation of enzymes involved in nucleotide cycle in photoreceptors. Inhibits the basal catalytic activity and the GCAP-stimulated activity of GUCY2D and GUCY2F, two retinal guanylyl cyclases involved in the production of cGMP in photoreceptors. Involved in the transport of GUCY2D and GUCY2F to their target sites in the photoreceptor outer segment. Up-regulates the activity of GUK1, a kinase that also plays an essential role for recycling GMP and indirectly, cGMP. Plays an important role for the survival of rods and cones in the retina.
• Tissue Specificity: Expressed in retina . Widely expressed (at protein level) . In the retina the strongest immunoreactivity is detected in the inner half of the cytoplasmic portion of the photoreceptor layer, where rods and cones are found, and the external half of the outer plexiform layer (at protein level) .

Molecular Interaction Atlas (MIA) of This DOT

9 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Leber congenital amaurosis 12	DIS0EIZY	Definitive	Autosomal recessive	[1]
Retinopathy	DISB4B0F	Definitive	Genetic Variation	[2]
Blindness	DISTIM10	Strong	Biomarker	[3]
Gonorrhea	DISQ5AO6	Strong	Biomarker	[4]
Leber congenital amaurosis 1	DISY2B33	Strong	Biomarker	[5]
Neoplasm	DISZKGEW	Strong	Biomarker	[4]
Neuroblastoma	DISVZBI4	Strong	Biomarker	[4]
Retinitis pigmentosa	DISCGPY8	Strong	Genetic Variation	[6]
Leber congenital amaurosis	DISMGH8F	Supportive	Autosomal dominant	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of Protein RD3 (RD3).	[7]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Protein RD3 (RD3).	[9]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Protein RD3 (RD3).	[7]
Permethrin	DMZ0Q1G	Approved	Permethrin decreases the expression of Protein RD3 (RD3).	[10]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Protein RD3 (RD3).	[11]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Protein RD3 (RD3).	[8]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Protein RD3 (RD3).	[12]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Protein RD3 (RD3).	[13]

References

• [1] Union makes strength: a worldwide collaborative genetic and clinical study to provide a comprehensive survey of RD3 mutations and delineate the associated phenotype. PLoS One. 2013;8(1):e51622. doi: 10.1371/journal.pone.0051622. Epub 2013 Jan 7.
• [2] Premature truncation of a novel protein, RD3, exhibiting subnuclear localization is associated with retinal degeneration. Am J Hum Genet. 2006 Dec;79(6):1059-70. doi: 10.1086/510021. Epub 2006 Oct 23.
• [3] Retinal degeneration 3 (RD3) protein, a retinal guanylyl cyclase regulator, forms a monomeric and elongated four-helix bundle.J Biol Chem. 2019 Feb 15;294(7):2318-2328. doi: 10.1074/jbc.RA118.006106. Epub 2018 Dec 17.
• [4] Retinal Degeneration Protein 3 (RD3) in normal human tissues: Novel insights.Sci Rep. 2017 Oct 13;7(1):13154. doi: 10.1038/s41598-017-13337-9.
• [5] Impaired association of retinal degeneration-3 with guanylate cyclase-1 and guanylate cyclase-activating protein-1 leads to leber congenital amaurosis-1.J Biol Chem. 2015 Feb 6;290(6):3488-99. doi: 10.1074/jbc.M114.616656. Epub 2014 Dec 4.
• [6] Identification and characterization of C1orf36, a transcript highly expressed in photoreceptor cells, and mutation analysis in retinitis pigmentosa.Biochem Biophys Res Commun. 2003 Aug 29;308(3):414-21. doi: 10.1016/s0006-291x(03)01410-4.
• [7] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [8] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [9] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [10] Exposure to Insecticides Modifies Gene Expression and DNA Methylation in Hematopoietic Tissues In Vitro. Int J Mol Sci. 2023 Mar 26;24(7):6259. doi: 10.3390/ijms24076259.
• [11] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [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] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.