Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT6Z069I)

• DOT Name: Protein fantom (RPGRIP1L)
• Synonyms: Nephrocystin-8; RPGR-interacting protein 1-like protein; RPGRIP1-like protein
• Gene Name: RPGRIP1L
• Related Disease:
  Cerebellar disorder
  Essential tremor
  Meckel syndrome, type 5
  Primary ciliary dyskinesia
  Bipolar disorder
  Ciliopathy
  Congestive heart failure
  Corpus callosum, agenesis of
  Disorder of orbital region
  Hepatocellular carcinoma
  Joubert syndrome 7
  Joubert syndrome with oculorenal defect
  Meckel syndrome, type 1
  Neoplasm
  Nephronophthisis
  Non-insulin dependent diabetes
  Obesity
  Vascular dementia
  Nephropathy
  Pemphigus vulgaris
  Retinal degeneration
  Joubert syndrome with renal defect
  Meckel syndrome
  Obsolete COACH syndrome 1
  Senior-Loken syndrome
  COACH syndrome
  Johanson-Blizzard syndrome
  Leber congenital amaurosis
  Timothy syndrome
  Tourette syndrome
  Tuberous sclerosis
  Vitiligo
• UniProt ID: FTM_HUMAN
• PDB ID: 2YRB
• Pfam ID: PF00168 ; PF11618 ; PF18111
• Sequence:
  MSGPTDETAGDLPVKDTGLNLFGMGGLQETSTTRTMKSRQAVSRVSREELEDRFLRLHDE
  NILLKQHARKQEDKIKRMATKLIRLVNDKKRYERVGGGPKRLGRDVEMEEMIEQLQEKVH
  ELEKQNETLKNRLISAKQQLQTQGYRQTPYNNVQSRINTGRRKANENAGLQECPRKGIKF
  QDADVAETPHPMFTKYGNSLLEEARGEIRNLENVIQSQRGQIEELEHLAEILKTQLRRKE
  NEIELSLLQLREQQATDQRSNIRDNVEMIKLHKQLVEKSNALSAMEGKFIQLQEKQRTLR
  ISHDALMANGDELNMQLKEQRLKCCSLEKQLHSMKFSERRIEELQDRINDLEKERELLKE
  NYDKLYDSAFSAAHEEQWKLKEQQLKVQIAQLETALKSDLTDKTEILDRLKTERDQNEKL
  VQENRELQLQYLEQKQQLDELKKRIKLYNQENDINADELSEALLLIKAQKEQKNGDLSFL
  VKVDSEINKDLERSMRELQATHAETVQELEKTRNMLIMQHKINKDYQMEVEAVTRKMENL
  QQDYELKVEQYVHLLDIRAARIHKLEAQLKDIAYGTKQYKFKPEIMPDDSVDEFDETIHL
  ERGENLFEIHINKVTFSSEVLQASGDKEPVTFCTYAFYDFELQTTPVVRGLHPEYNFTSQ
  YLVHVNDLFLQYIQKNTITLEVHQAYSTEYETIAACQLKFHEILEKSGRIFCTASLIGTK
  GDIPNFGTVEYWFRLRVPMDQAIRLYRERAKALGYITSNFKGPEHMQSLSQQAPKTAQLS
  STDSTDGNLNELHITIRCCNHLQSRASHLQPHPYVVYKFFDFADHDTAIIPSSNDPQFDD
  HMYFPVPMNMDLDRYLKSESLSFYVFDDSDTQENIYIGKVNVPLISLAHDRCISGIFELT
  DHQKHPAGTIHVILKWKFAYLPPSGSITTEDLGNFIRSEEPEVVQRLPPASSVSTLVLAP
  RPKPRQRLTPVDKKVSFVDIMPHQSDETSPPPEDRKEISPEVEHIPEIEINMLTVPHVPK
  VSQEGSVDEVKENTEKMQQGKDDVSLLSEGQLAEQSLASSEDETEITEDLEPEVEEDMSA
  SDSDDCIIPGPISKNIKQSLALSPGLGCSSAISAHCNFRLPGSSDFPASASQVDGITGAC
  HHTQPSEKIRIEIIALSLNDSQVTMDDTIQRLFVECRFYSLPAEETPVSLPKPKSGQWVY
  YNYSNVIYVDKENNKAKRDILKAILQKQEMPNRSLRFTVVSDPPEDEQDLECEDIGVAHV
  DLADMFQEGRDLIEQNIDVFDARADGEGIGKLRVTVEALHALQSVYKQYRDDLEA
• Function: Negatively regulates signaling through the G-protein coupled thromboxane A2 receptor (TBXA2R). May be involved in mechanisms like programmed cell death, craniofacial development, patterning of the limbs, and formation of the left-right axis. Involved in the organization of apical junctions; the function is proposed to implicate a NPHP1-4-8 module. Does not seem to be strictly required for ciliogenesis. Involved in establishment of planar cell polarity such as in cochlear sensory epithelium and is proposed to implicate stabilization of disheveled proteins. Involved in regulation of proteasomal activity at the primary cilium probably implicating association with PSDM2.
• Tissue Specificity: Ubiquitously expressed with relatively high level of expression in hypothalamus and islet. During early development, expressed in multiple organs including brain, eye, forelimb and kidney.
• Reactome Pathway:
  Anchoring of the basal body to the plasma membrane (R-HSA-5620912)
  Hedgehog 'off' state (R-HSA-5610787)

Molecular Interaction Atlas (MIA) of This DOT

32 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Cerebellar disorder	DIS2O7WM	Definitive	Biomarker	[1]
Essential tremor	DIS7GBKQ	Definitive	Genetic Variation	[2]
Meckel syndrome, type 5	DISQ5VD8	Definitive	Autosomal recessive	[3]
Primary ciliary dyskinesia	DISOBC7V	Definitive	Biomarker	[1]
Bipolar disorder	DISAM7J2	Strong	Genetic Variation	[4]
Ciliopathy	DIS10G4I	Strong	Biomarker	[5]
Congestive heart failure	DIS32MEA	Strong	Genetic Variation	[6]
Corpus callosum, agenesis of	DISO9P40	Strong	Biomarker	[7]
Disorder of orbital region	DISH0ECJ	Strong	Biomarker	[1]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[8]
Joubert syndrome 7	DISMRTBS	Strong	Autosomal recessive	[1]
Joubert syndrome with oculorenal defect	DISU0IPO	Strong	Genetic Variation	[1]
Meckel syndrome, type 1	DIS4YWZU	Strong	Biomarker	[7]
Neoplasm	DISZKGEW	Strong	Biomarker	[8]
Nephronophthisis	DISXU4HY	Strong	Genetic Variation	[9]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Genetic Variation	[10]
Obesity	DIS47Y1K	Strong	Genetic Variation	[11]
Vascular dementia	DISVO82H	Strong	Biomarker	[12]
Nephropathy	DISXWP4P	moderate	Biomarker	[1]
Pemphigus vulgaris	DISENR62	moderate	Biomarker	[13]
Retinal degeneration	DISM1JHQ	moderate	Biomarker	[14]
Joubert syndrome with renal defect	DIS52E3N	Supportive	Autosomal recessive	[15]
Meckel syndrome	DISXPHOY	Supportive	Autosomal recessive	[16]
Obsolete COACH syndrome 1	DISM57KK	Supportive	Autosomal recessive	[17]
Senior-Loken syndrome	DISGBSGP	Disputed	Genetic Variation	[18]
COACH syndrome	DISVDRSD	Limited	Biomarker	[17]
Johanson-Blizzard syndrome	DISYNPE8	Limited	Genetic Variation	[19]
Leber congenital amaurosis	DISMGH8F	Limited	Biomarker	[18]
Timothy syndrome	DISBXBZP	Limited	Biomarker	[20]
Tourette syndrome	DISX9D54	Limited	Biomarker	[20]
Tuberous sclerosis	DISEMUGZ	Limited	Biomarker	[20]
Vitiligo	DISR05SL	Limited	Genetic Variation	[21]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Protein fantom (RPGRIP1L).	[22]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Protein fantom (RPGRIP1L).	[23]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Protein fantom (RPGRIP1L).	[24]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Protein fantom (RPGRIP1L).	[25]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Protein fantom (RPGRIP1L).	[26]
Acocantherin	DM7JT24	Approved	Acocantherin decreases the expression of Protein fantom (RPGRIP1L).	[27]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Protein fantom (RPGRIP1L).	[28]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Protein fantom (RPGRIP1L).	[29]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Protein fantom (RPGRIP1L).	[30]
OXYQUINOLINE	DMZVS9Y	Investigative	OXYQUINOLINE decreases the expression of Protein fantom (RPGRIP1L).	[26]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Protein fantom (RPGRIP1L).	[31]

References

• [1] The ciliary gene RPGRIP1L is mutated in cerebello-oculo-renal syndrome (Joubert syndrome type B) and Meckel syndrome. Nat Genet. 2007 Jul;39(7):875-81. doi: 10.1038/ng2039. Epub 2007 Jun 10.
• [2] Role of altered cerebello-thalamo-cortical network in the neurobiology of essential tremor.Neuroradiology. 2017 Feb;59(2):157-168. doi: 10.1007/s00234-016-1771-1. Epub 2017 Jan 6.
• [3] RPGRIP1L mutations are mainly associated with the cerebello-renal phenotype of Joubert syndrome-related disorders. Clin Genet. 2008 Aug;74(2):164-70. doi: 10.1111/j.1399-0004.2008.01047.x. Epub 2008 Jun 28.
• [4] Propensity score-based nonparametric test revealing genetic variants underlying bipolar disorder.Genet Epidemiol. 2011 Feb;35(2):125-32. doi: 10.1002/gepi.20558.
• [5] A multiscale mathematical model of cell dynamics during neurogenesis in the mouse cerebral cortex.BMC Bioinformatics. 2019 Sep 14;20(1):470. doi: 10.1186/s12859-019-3018-8.
• [6] MKS3/TMEM67 mutations are a major cause of COACH Syndrome, a Joubert Syndrome related disorder with liver involvement.Hum Mutat. 2009 Feb;30(2):E432-42. doi: 10.1002/humu.20924.
• [7] The role of primary cilia in corpus callosum formation is mediated by production of the Gli3 repressor.Hum Mol Genet. 2015 Sep 1;24(17):4997-5014. doi: 10.1093/hmg/ddv221. Epub 2015 Jun 12.
• [8] The basal body gene, RPGRIP1L, is a candidate tumour suppressor gene in human hepatocellular carcinoma.Eur J Cancer. 2009 Jul;45(11):2041-9. doi: 10.1016/j.ejca.2009.04.012. Epub 2009 May 4.
• [9] Expanding Phenotype of Nephronophthisis-Related Ciliopathy: an Elderly Patient with Homozygous RPGRIP1L Mutation.Nephron. 2018;140(1):74-78. doi: 10.1159/000490770. Epub 2018 Jul 10.
• [10] Genetic Variants in HSD17B3, SMAD3, and IPO11 Impact Circulating Lipids in Response to Fenofibrate in Individuals With Type 2 Diabetes.Clin Pharmacol Ther. 2018 Apr;103(4):712-721. doi: 10.1002/cpt.798. Epub 2017 Nov 3.
• [11] Ciliary gene RPGRIP1L is required for hypothalamic arcuate neuron development.JCI Insight. 2019 Feb 7;4(3):e123337. doi: 10.1172/jci.insight.123337.
• [12] 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.
• [13] RPGRIP1L is required for stabilizing epidermal keratinocyte adhesion through regulating desmoglein endocytosis.PLoS Genet. 2019 Jan 28;15(1):e1007914. doi: 10.1371/journal.pgen.1007914. eCollection 2019 Jan.
• [14] 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.
• [15] Joubert Syndrome and related disorders. Orphanet J Rare Dis. 2010 Jul 8;5:20. doi: 10.1186/1750-1172-5-20.
• [16] Molecular genetics and pathogenic mechanisms for the severe ciliopathies: insights into neurodevelopment and pathogenesis of neural tube defects. Mol Neurobiol. 2011 Feb;43(1):12-26. doi: 10.1007/s12035-010-8154-0. Epub 2010 Nov 27.
• [17] Mutations in 3 genes (MKS3, CC2D2A and RPGRIP1L) cause COACH syndrome (Joubert syndrome with congenital hepatic fibrosis). J Med Genet. 2010 Jan;47(1):8-21. doi: 10.1136/jmg.2009.067249. Epub 2009 Jul 1.
• [18] Mutations in the gene encoding the basal body protein RPGRIP1L, a nephrocystin-4 interactor, cause Joubert syndrome.Nat Genet. 2007 Jul;39(7):882-8. doi: 10.1038/ng2069. Epub 2007 Jun 10.
• [19] CC2D2A mutations in Meckel and Joubert syndromes indicate a genotype-phenotype correlation.Hum Mutat. 2009 Nov;30(11):1574-82. doi: 10.1002/humu.21116.
• [20] Nipple-Areolar Complex Position in Female-to-Male Transsexuals After Non-skin-excisional Mastectomy: A Case-Control Study in Japan.Aesthetic Plast Surg. 2019 Oct;43(5):1195-1203. doi: 10.1007/s00266-019-01409-2. Epub 2019 May 29.
• [21] Three new single nucleotide polymorphisms identified by a genome-wide association study in Korean patients with vitiligo.J Korean Med Sci. 2013 May;28(5):775-9. doi: 10.3346/jkms.2013.28.5.775. Epub 2013 May 2.
• [22] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [23] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [24] 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.
• [25] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [26] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [27] Ouabain at pathological concentrations might induce damage in human vascular endothelial cells. Acta Pharmacol Sin. 2006 Feb;27(2):165-72. doi: 10.1111/j.1745-7254.2006.00244.x.
• [28] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [29] 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.
• [30] 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.
• [31] 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.