Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTWUA2AV)

• DOT Name: G-protein coupled receptor 143 (GPR143)
• Synonyms: Ocular albinism type 1 protein
• Gene Name: GPR143
• Related Disease:
  Inherited retinal dystrophy
  Acquired nystagmus
  Albinism
  Aniridia
  Colon cancer
  Colorectal adenocarcinoma
  Colorectal cancer
  Colorectal cancer, susceptibility to, 1
  Colorectal cancer, susceptibility to, 10
  Colorectal cancer, susceptibility to, 12
  Colorectal carcinoma
  Colorectal neoplasm
  Hypopigmentation of the skin
  Melanoma
  Nystagmus 6, congenital, X-linked
  Ocular albinism
  Oculocutaneous albinism
  Oculocutaneous albinism type 2
  Parkinson disease
  Pathologic nystagmus
  Pheochromocytoma
  Sensorineural hearing loss disorder
  X-linked recessive ocular albinism
  Disorder of orbital region
• UniProt ID: GP143_HUMAN
• Pfam ID: PF02101
• Sequence:
  MASPRLGTFCCPTRDAATQLVLSFQPRAFHALCLGSGGLRLALGLLQLLPGRRPAGPGSP
  ATSPPASVRILRAAAACDLLGCLGMVIRSTVWLGFPNFVDSVSDMNHTEIWPAAFCVGSA
  MWIQLLYSACFWWLFCYAVDAYLVIRRSAGLSTILLYHIMAWGLATLLCVEGAAMLYYPS
  VSRCERGLDHAIPHYVTMYLPLLLVLVANPILFQKTVTAVASLLKGRQGIYTENERRMGA
  VIKIRFFKIMLVLIICWLSNIINESLLFYLEMQTDINGGSLKPVRTAAKTTWFIMGILNP
  AQGFLLSLAFYGWTGCSLGFQSPRKEIQWESLTTSAAEGAHPSPLMPHENPASGKVSQVG
  GQTSDEALSMLSEGSDASTIEIHTASESCNKNEGDPALPTHGDL
• Function: Receptor for tyrosine, L-DOPA and dopamine. After binding to L-DOPA, stimulates Ca(2+) influx into the cytoplasm, increases secretion of the neurotrophic factor SERPINF1 and relocalizes beta arrestin at the plasma membrane; this ligand-dependent signaling occurs through a G(q)-mediated pathway in melanocytic cells. Its activity is mediated by G proteins which activate the phosphoinositide signaling pathway. Also plays a role as an intracellular G protein-coupled receptor involved in melanosome biogenesis, organization and transport.
• Tissue Specificity: Expressed at high levels in the retina, including the retinal pigment epithelium (RPE), and in melanocytes. Weak expression is observed in brain and adrenal gland.
• Reactome Pathway:
  G alpha (q) signalling events (R-HSA-416476)
  Amine ligand-binding receptors (R-HSA-375280)

Molecular Interaction Atlas (MIA) of This DOT

24 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Inherited retinal dystrophy	DISGGL77	Definitive	X-linked	[1]
Acquired nystagmus	DISMYF5H	Strong	Genetic Variation	[2]
Albinism	DIS5D82I	Strong	Biomarker	[3]
Aniridia	DIS1P333	Strong	Genetic Variation	[4]
Colon cancer	DISVC52G	Strong	Genetic Variation	[5]
Colorectal adenocarcinoma	DISPQOUB	Strong	Genetic Variation	[5]
Colorectal cancer	DISNH7P9	Strong	Genetic Variation	[5]
Colorectal cancer, susceptibility to, 1	DISZ794C	Strong	Genetic Variation	[5]
Colorectal cancer, susceptibility to, 10	DISQXMYM	Strong	Genetic Variation	[5]
Colorectal cancer, susceptibility to, 12	DIS4FXJX	Strong	Genetic Variation	[5]
Colorectal carcinoma	DIS5PYL0	Strong	Genetic Variation	[5]
Colorectal neoplasm	DISR1UCN	Strong	Genetic Variation	[5]
Hypopigmentation of the skin	DIS39YKC	Strong	Biomarker	[6]
Melanoma	DIS1RRCY	Strong	Altered Expression	[7]
Nystagmus 6, congenital, X-linked	DISJZIWH	Strong	X-linked	[8]
Ocular albinism	DIS5IHK1	Strong	Genetic Variation	[9]
Oculocutaneous albinism	DISJS7CU	Strong	Biomarker	[3]
Oculocutaneous albinism type 2	DISMTYMP	Strong	Genetic Variation	[10]
Parkinson disease	DISQVHKL	Strong	Biomarker	[11]
Pathologic nystagmus	DIS1QSPO	Strong	Genetic Variation	[12]
Pheochromocytoma	DIS56IFV	Strong	Altered Expression	[13]
Sensorineural hearing loss disorder	DISJV45Z	Strong	Genetic Variation	[14]
X-linked recessive ocular albinism	DISI9S32	Strong	X-linked	[15]
Disorder of orbital region	DISH0ECJ	Limited	Biomarker	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of G-protein coupled receptor 143 (GPR143).	[16]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of G-protein coupled receptor 143 (GPR143).	[22]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of G-protein coupled receptor 143 (GPR143).	[24]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of G-protein coupled receptor 143 (GPR143).	[17]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of G-protein coupled receptor 143 (GPR143).	[17]
Decitabine	DMQL8XJ	Approved	Decitabine decreases the expression of G-protein coupled receptor 143 (GPR143).	[18]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of G-protein coupled receptor 143 (GPR143).	[19]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of G-protein coupled receptor 143 (GPR143).	[20]
Belinostat	DM6OC53	Phase 2	Belinostat decreases the expression of G-protein coupled receptor 143 (GPR143).	[21]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of G-protein coupled receptor 143 (GPR143).	[23]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde increases the expression of G-protein coupled receptor 143 (GPR143).	[25]

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] A novel GPR143 duplication mutation in a Chinese family with X-linked congenital nystagmus.Mol Vis. 2009;15:810-4. Epub 2009 Apr 22.
• [3] In silico analysis of miRNA-mediated gene regulation in OCA and OA genes.Cell Biochem Biophys. 2014 Dec;70(3):1923-32. doi: 10.1007/s12013-014-0152-9.
• [4] Isolated foveal hypoplasia: report of a new case and detailed genetic investigation.Int Ophthalmol. 2011 Apr;31(2):117-20. doi: 10.1007/s10792-011-9424-1. Epub 2011 Jan 25.
• [5] Common variation near CDKN1A, POLD3 and SHROOM2 influences colorectal cancer risk.Nat Genet. 2012 May 27;44(7):770-6. doi: 10.1038/ng.2293.
• [6] GPR143 mutational analysis in two Italian families with X-linked ocular albinism.Genet Test Mol Biomarkers. 2009 Aug;13(4):527-31. doi: 10.1089/gtmb.2009.0030.
• [7] Normal tissue depresses while tumor tissue enhances human T cell responses in vivo to a novel self/tumor melanoma antigen, OA1.J Immunol. 2003 Feb 1;170(3):1579-85. doi: 10.4049/jimmunol.170.3.1579.
• [8] Identification of a novel GPR143 deletion in a Chinese family with X-linked congenital nystagmus. Mol Vis. 2008 May 30;14:1015-9.
• [9] Molecular genetic and clinical evaluation of three Chinese families with X-linked ocular albinism.Sci Rep. 2017 Feb 17;7:33713. doi: 10.1038/srep33713.
• [10] Spectrum of candidate gene mutations associated with Indian familial oculocutaneous and ocular albinism.Mol Vis. 2010 Aug 9;16:1514-24.
• [11] Immunoreactivity of a G protein-coupled l-DOPA receptor GPR143, in Lewy bodies.Neurosci Res. 2019 Nov;148:49-53. doi: 10.1016/j.neures.2018.12.004. Epub 2018 Dec 24.
• [12] GPR143 Gene Mutations in Five Chinese Families with X-linked Congenital Nystagmus.Sci Rep. 2015 Jul 10;5:12031. doi: 10.1038/srep12031.
• [13] Overexpression of the gene product of ocular albinism 1 (GPR143/OA1) but not its mutant forms inhibits neurite outgrowth in PC12cells.J Pharmacol Sci. 2019 Sep;141(1):41-48. doi: 10.1016/j.jphs.2019.09.002. Epub 2019 Sep 11.
• [14] Ocular albinism with infertility and late-onset sensorineural hearing loss.Am J Med Genet A. 2018 Jul;176(7):1587-1593. doi: 10.1002/ajmg.a.38836.
• [15] Abnormal crossing of the optic fibres shown by evoked magnetic fields in patients with ocular albinism with a novel mutation in the OA1 gene. Br J Ophthalmol. 2005 Jul;89(7):820-4. doi: 10.1136/bjo.2004.060582.
• [16] 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.
• [17] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [18] Decitabine up-regulates S100A2 expression and synergizes with IFN-gamma to kill uveal melanoma cells. Clin Cancer Res. 2007 Sep 1;13(17):5219-25. doi: 10.1158/1078-0432.CCR-07-0816.
• [19] Temporal changes in gene expression in the skin of patients treated with isotretinoin provide insight into its mechanism of action. Dermatoendocrinol. 2009 May;1(3):177-87.
• [20] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [21] 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.
• [22] 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.
• [23] 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.
• [24] 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.
• [25] Transcriptome profile analysis of saturated aliphatic aldehydes reveals carbon number-specific molecules involved in pulmonary toxicity. Chem Res Toxicol. 2014 Aug 18;27(8):1362-70.