Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTG0L2CE)

• DOT Name: Protein crumbs homolog 2 (CRB2)
• Synonyms: Crumbs-like protein 2
• Gene Name: CRB2
• Related Disease:
  Familial nephrotic syndrome
  Focal segmental glomerulosclerosis 9
  Nephropathy
  Ventriculomegaly-cystic kidney disease
  Blindness
  Ciliopathy
  Congenital nephrotic syndrome, Finnish type
  Disorder of orbital region
  Hydrocephalus
  Inherited retinal dystrophy
  Leber congenital amaurosis 1
  Leber congenital amaurosis 8
  Nephrotic syndrome, type 2
  Steroid-resistant nephrotic syndrome
  Nephrotic syndrome
  Familial idiopathic steroid-resistant nephrotic syndrome
  Focal segmental glomerulosclerosis
  Leber congenital amaurosis
  Retinitis pigmentosa
  Retinopathy
• UniProt ID: CRUM2_HUMAN
• PDB ID: 2WO6
• Pfam ID: PF00008 ; PF12661 ; PF02210
• Sequence:
  MALARPGTPDPQALASVLLLLLWAPALSLLAGTVPSEPPSACASDPCAPGTECQATESGG
  YTCGPMEPRGCATQPCHHGALCVPQGPDPTGFRCYCVPGFQGPRCELDIDECASRPCHHG
  ATCRNLADRYECHCPLGYAGVTCEMEVDECASAPCLHGGSCLDGVGSFRCVCAPGYGGTR
  CQLDLDECQSQPCAHGGTCHDLVNGFRCDCAGTGYEGTHCEREVLECASAPCEHNASCLE
  GLGSFRCLCWPGYSGELCEVDEDECASSPCQHGGRCLQRSDPALYGGVQAAFPGAFSFRH
  AAGFLCHCPPGFEGADCGVEVDECASRPCLNGGHCQDLPNGFQCHCPDGYAGPTCEEDVD
  ECLSDPCLHGGTCSDTVAGYICRCPETWGGRDCSVQLTGCQGHTCPLAATCIPIFESGVH
  SYVCHCPPGTHGPFCGQNTTFSVMAGSPIQASVPAGGPLGLALRFRTTLPAGTLATRNDT
  KESLELALVAATLQATLWSYSTTVLVLRLPDLALNDGHWHQVEVVLHLATLELRLWHEGC
  PARLCVASGPVALASTASATPLPAGISSAQLGDATFAGCLQDVRVDGHLLLPEDLGENVL
  LGCERREQCRPLPCVHGGSCVDLWTHFRCDCARPHRGPTCADEIPAATFGLGGAPSSASF
  LLQELPGPNLTVSFLLRTRESAGLLLQFANDSAAGLTVFLSEGRIRAEVPGSPAVVLPGR
  WDDGLRHLVMLSFGPDQLQDLGQHVHVGGRLLAADSQPWGGPFRGCLQDLRLDGCHLPFF
  PLPLDNSSQPSELGGRQSWNLTAGCVSEDMCSPDPCFNGGTCLVTWNDFHCTCPANFTGP
  TCAQQLWCPGQPCLPPATCEEVPDGFVCVAEATFREGPPAAFSGHNASSGRLLGGLSLAF
  RTRDSEAWLLRAAAGALEGVWLAVRNGSLAGGVRGGHGLPGAVLPIPGPRVADGAWHRVR
  LAMERPAATTSRWLLWLDGAATPVALRGLASDLGFLQGPGAVRILLAENFTGCLGRVALG
  GLPLPLARPRPGAAPGAREHFASWPGTPAPILGCRGAPVCAPSPCLHDGACRDLFDAFAC
  ACGPGWEGPRCEAHVDPCHSAPCARGRCHTHPDGRFECRCPPGFGGPRCRLPVPSKECSL
  NVTCLDGSPCEGGSPAANCSCLEGLAGQRCQVPTLPCEANPCLNGGTCRAAGGVSECICN
  ARFSGQFCEVAKGLPLPLPFPLLEVAVPAACACLLLLLLGLLSGILAARKRRQSEGTYSP
  SQQEVAGARLEMDSVLKVPPEERLI
• Function: Apical polarity protein that plays a central role during the epithelial-to-mesenchymal transition (EMT) at gastrulation, when newly specified mesodermal cells move inside the embryo. Acts by promoting cell ingression, the process by which cells leave the epithelial epiblast and move inside the embryo to form a new tissue layer. The anisotropic distribution of CRB2 and MYH10/myosin-IIB at cell edges define which cells will ingress: cells with high apical CRB2 are probably extruded from the epiblast by neighboring cells with high levels of apical MYH10/myosin-IIB. Plays a role in the maintenance of retinal neuroepithelium organization, structural integrity, adhesion, photoreceptor polarity and retinal photoreceptor layer thickness. May play a role in determining the length of cone photoreceptor outer segments and proliferation of late-born progenitor cells. Also required for maintenance of the apical polarity complex during development of the cortex. Inhibits gamma-secretase-dependent cleavage of APP and secretion of amyloid-beta peptide 40 and amyloid-beta peptide 42, and thereby inhibits gamma-secretase-dependent Notch transcription.
• Tissue Specificity: Expressed in glomeruli, podocytes of the glomerular capillary loops, and parietal glomerular epithelial cells in the kidney (at protein level) . Expressed in retina, fetal eye and brain . Also expressed in kidney, RPE/choroid, and at low levels in lung, placenta, and heart .
• KEGG Pathway: Hippo sig.ling pathway (hsa04390)

Molecular Interaction Atlas (MIA) of This DOT

20 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Familial nephrotic syndrome	DISADF8G	Definitive	Genetic Variation	[1]
Focal segmental glomerulosclerosis 9	DISQNU6J	Definitive	Autosomal recessive	[2]
Nephropathy	DISXWP4P	Definitive	Genetic Variation	[3]
Ventriculomegaly-cystic kidney disease	DISFOWVC	Definitive	Autosomal recessive	[4]
Blindness	DISTIM10	Strong	Biomarker	[5]
Ciliopathy	DIS10G4I	Strong	Biomarker	[6]
Congenital nephrotic syndrome, Finnish type	DIS8P7EH	Strong	Genetic Variation	[6]
Disorder of orbital region	DISH0ECJ	Strong	Biomarker	[7]
Hydrocephalus	DISIZUF7	Strong	Biomarker	[6]
Inherited retinal dystrophy	DISGGL77	Strong	Genetic Variation	[8]
Leber congenital amaurosis 1	DISY2B33	Strong	Biomarker	[9]
Leber congenital amaurosis 8	DIS3ICT1	Strong	Biomarker	[10]
Nephrotic syndrome, type 2	DISIRFO1	Strong	GermlineCausalMutation	[11]
Steroid-resistant nephrotic syndrome	DISVEBC9	Strong	Genetic Variation	[12]
Nephrotic syndrome	DISSPSC2	moderate	Genetic Variation	[11]
Familial idiopathic steroid-resistant nephrotic syndrome	DISQ53RS	Supportive	Autosomal dominant	[11]
Focal segmental glomerulosclerosis	DISJNHH0	Limited	Biomarker	[12]
Leber congenital amaurosis	DISMGH8F	Limited	Biomarker	[9]
Retinitis pigmentosa	DISCGPY8	Limited	Biomarker	[9]
Retinopathy	DISB4B0F	Limited	Biomarker	[13]

2 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 Protein crumbs homolog 2 (CRB2).	[14]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Protein crumbs homolog 2 (CRB2).	[19]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Protein crumbs homolog 2 (CRB2).	[15]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Protein crumbs homolog 2 (CRB2).	[16]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Protein crumbs homolog 2 (CRB2).	[17]
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the expression of Protein crumbs homolog 2 (CRB2).	[16]
Niclosamide	DMJAGXQ	Approved	Niclosamide increases the expression of Protein crumbs homolog 2 (CRB2).	[18]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Protein crumbs homolog 2 (CRB2).	[20]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Protein crumbs homolog 2 (CRB2).	[21]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Protein crumbs homolog 2 (CRB2).	[22]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Protein crumbs homolog 2 (CRB2).	[23]

References

• [1] Association of crumbs homolog-2 with mTORC1 in developing podocyte.PLoS One. 2018 Aug 20;13(8):e0202400. doi: 10.1371/journal.pone.0202400. eCollection 2018.
• [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] Expanding the phenotype of CRB2 mutations-A new ciliopathy syndrome?.Clin Genet. 2016 Dec;90(6):540-544. doi: 10.1111/cge.12764. Epub 2016 May 2.
• [4] CRB2 mutations produce a phenotype resembling congenital nephrosis, Finnish type, with cerebral ventriculomegaly and raised alpha-fetoprotein. Am J Hum Genet. 2015 Jan 8;96(1):162-9. doi: 10.1016/j.ajhg.2014.11.013. Epub 2014 Dec 31.
• [5] CRB2 Loss in Rod Photoreceptors Is Associated with Progressive Loss of Retinal Contrast Sensitivity.Int J Mol Sci. 2019 Aug 21;20(17):4069. doi: 10.3390/ijms20174069.
• [6] Expansion of phenotype and genotypic data in CRB2-related syndrome.Eur J Hum Genet. 2016 Oct;24(10):1436-44. doi: 10.1038/ejhg.2016.24. Epub 2016 Mar 23.
• [7] Gene therapy into photoreceptors and Mller glial cells restores retinal structure and function in CRB1 retinitis pigmentosa mouse models.Hum Mol Genet. 2015 Jun 1;24(11):3104-18. doi: 10.1093/hmg/ddv062. Epub 2015 Feb 20.
• [8] CRB2 acts as a modifying factor of CRB1-related retinal dystrophies in mice.Hum Mol Genet. 2014 Jul 15;23(14):3759-71. doi: 10.1093/hmg/ddu089. Epub 2014 Feb 23.
• [9] Loss of CRB2 in Mller glial cells modifies a CRB1-associated retinitis pigmentosa phenotype into a Leber congenital amaurosis phenotype.Hum Mol Genet. 2019 Jan 1;28(1):105-123. doi: 10.1093/hmg/ddy337.
• [10] Targeted deletion of Crb1/Crb2 in the optic vesicle models key features of leber congenital amaurosis 8.Dev Biol. 2019 Sep 15;453(2):141-154. doi: 10.1016/j.ydbio.2019.05.008. Epub 2019 May 28.
• [11] Defects of CRB2 cause steroid-resistant nephrotic syndrome. Am J Hum Genet. 2015 Jan 8;96(1):153-61. doi: 10.1016/j.ajhg.2014.11.014. Epub 2014 Dec 31.
• [12] Long-term clinicopathologic observation in a case of steroid-resistant nephrotic syndrome caused by a novel Crumbs homolog 2 mutation.Nephrology (Carlton). 2018 Jul;23(7):697-702. doi: 10.1111/nep.13244.
• [13] CRB2 mutation causes autosomal recessive retinitis pigmentosa.Exp Eye Res. 2019 Mar;180:164-173. doi: 10.1016/j.exer.2018.12.018. Epub 2018 Dec 26.
• [14] 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.
• [15] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [16] Arsenite and cadmium promote the development of mammary tumors. Carcinogenesis. 2020 Jul 14;41(7):1005-1014. doi: 10.1093/carcin/bgz176.
• [17] 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.
• [18] Mitochondrial Uncoupling Induces Epigenome Remodeling and Promotes Differentiation in Neuroblastoma. Cancer Res. 2023 Jan 18;83(2):181-194. doi: 10.1158/0008-5472.CAN-22-1029.
• [19] Effect of aflatoxin B(1), benzo[a]pyrene, and methapyrilene on transcriptomic and epigenetic alterations in human liver HepaRG cells. Food Chem Toxicol. 2018 Nov;121:214-223. doi: 10.1016/j.fct.2018.08.034. Epub 2018 Aug 26.
• [20] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
• [21] 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.
• [22] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [23] Regulation of chromatin assembly and cell transformation by formaldehyde exposure in human cells. Environ Health Perspect. 2017 Sep 21;125(9):097019.