Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTXYUNG0)

• DOT Name: Protein crumbs homolog 1 (CRB1)
• Gene Name: CRB1
• Related Disease:
  Leber congenital amaurosis 8
  Retinitis pigmentosa 12
  Achromatopsia
  Achromatopsia 3
  Autosomal recessive bestrophinopathy
  Blindness
  Cone-rod dystrophy 2
  Congenital stationary night blindness 2A
  Enhanced S-cone syndrome
  Immunodeficiency
  Keratoconus
  Major depressive disorder
  Polycystic ovarian syndrome
  Retinoblastoma
  Vascular disease
  Age-related macular degeneration
  Ankylosing spondylitis
  Asthma
  Autoimmune disease
  Autoimmune disease, susceptibility to, 6
  Autoimmune thyroid disease
  Coeliac disease
  Common variable immunodeficiency
  Crohn disease
  Hereditary macular dystrophy
  Immune system disorder
  Inherited retinal dystrophy
  Juvenile idiopathic arthritis
  Psoriasis
  STAT3-related early-onset multisystem autoimmune disease
  Systemic lupus erythematosus
  Type-1 diabetes
  Ulcerative colitis
  Leber congenital amaurosis
  Nanophthalmia
  Pigmented paravenous retinochoroidal atrophy
  Retinitis pigmentosa
  Stargardt disease
  Ciliopathy
  Cone-rod dystrophy
  Disorder of orbital region
  Microphthalmia
• UniProt ID: CRUM1_HUMAN
• PDB ID: 4UU5
• Pfam ID: PF00008 ; PF12661 ; PF02210
• Sequence:
  MALKNINYLLIFYLSFSLLIYIKNSFCNKNNTRCLSNSCQNNSTCKDFSKDNDCSCSDTA
  NNLDKDCDNMKDPCFSNPCQGSATCVNTPGERSFLCKCPPGYSGTICETTIGSCGKNSCQ
  HGGICHQDPIYPVCICPAGYAGRFCEIDHDECASSPCQNGAVCQDGIDGYSCFCVPGYQG
  RHCDLEVDECASDPCKNEATCLNEIGRYTCICPHNYSGVNCELEIDECWSQPCLNGATCQ
  DALGAYFCDCAPGFLGDHCELNTDECASQPCLHGGLCVDGENRYSCNCTGSGFTGTHCET
  LMPLCWSKPCHNNATCEDSVDNYTCHCWPGYTGAQCEIDLNECNSNPCQSNGECVELSSE
  KQYGRITGLPSSFSYHEASGYVCICQPGFTGIHCEEDVNECSSNPCQNGGTCENLPGNYT
  CHCPFDNLSRTFYGGRDCSDILLGCTHQQCLNNGTCIPHFQDGQHGFSCLCPSGYTGSLC
  EIATTLSFEGDGFLWVKSGSVTTKGSVCNIALRFQTVQPMALLLFRSNRDVFVKLELLSG
  YIHLSIQVNNQSKVLLFISHNTSDGEWHFVEVIFAEAVTLTLIDDSCKEKCIAKAPTPLE
  SDQSICAFQNSFLGGLPVGMTSNGVALLNFYNMPSTPSFVGCLQDIKIDWNHITLENISS
  GSSLNVKAGCVRKDWCESQPCQSRGRCINLWLSYQCDCHRPYEGPNCLREYVAGRFGQDD
  STGYVIFTLDESYGDTISLSMFVRTLQPSGLLLALENSTYQYIRVWLERGRLAMLTPNSP
  KLVVKFVLNDGNVHLISLKIKPYKIELYQSSQNLGFISASTWKIEKGDVIYIGGLPDKQE
  TELNGGFFKGCIQDVRLNNQNLEFFPNPTNNASLNPVLVNVTQGCAGDNSCKSNPCHNGG
  VCHSRWDDFSCSCPALTSGKACEEVQWCGFSPCPHGAQCQPVLQGFECIANAVFNGQSGQ
  ILFRSNGNITRELTNITFGFRTRDANVIILHAEKEPEFLNISIQDSRLFFQLQSGNSFYM
  LSLTSLQSVNDGTWHEVTLSMTDPLSQTSRWQMEVDNETPFVTSTIATGSLNFLKDNTDI
  YVGDRAIDNIKGLQGCLSTIEIGGIYLSYFENVHGFINKPQEEQFLKISTNSVVTGCLQL
  NVCNSNPCLHGGNCEDIYSSYHCSCPLGWSGKHCELNIDECFSNPCIHGNCSDRVAAYHC
  TCEPGYTGVNCEVDIDNCQSHQCANGATCISHTNGYSCLCFGNFTGKFCRQSRLPSTVCG
  NEKTNLTCYNGGNCTEFQTELKCMCRPGFTGEWCEKDIDECASDPCVNGGLCQDLLNKFQ
  CLCDVAFAGERCEVDLADDLISDIFTTIGSVTVALLLILLLAIVASVVTSNKRATQGTYS
  PSRQEKEGSRVEMWNLMPPPAMERLI
• Function: Plays a role in photoreceptor morphogenesis in the retina. May maintain cell polarization and adhesion.
• Tissue Specificity: Preferential expression in retina, also expressed in brain, testis, fetal brain and fetal eye . Expressed at the outer limiting membrane and apical to adherens junctions in the retina .
• KEGG Pathway: Hippo sig.ling pathway (hsa04390)

Molecular Interaction Atlas (MIA) of This DOT

42 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Leber congenital amaurosis 8	DIS3ICT1	Definitive	Autosomal recessive	[1]
Retinitis pigmentosa 12	DIS90SAO	Definitive	Autosomal recessive	[2]
Achromatopsia	DISKL51I	Strong	Genetic Variation	[3]
Achromatopsia 3	DISR4EMI	Strong	Genetic Variation	[3]
Autosomal recessive bestrophinopathy	DISU5FU5	Strong	Genetic Variation	[4]
Blindness	DISTIM10	Strong	Biomarker	[5]
Cone-rod dystrophy 2	DISX2RWY	Strong	Genetic Variation	[6]
Congenital stationary night blindness 2A	DISA57KI	Strong	Genetic Variation	[3]
Enhanced S-cone syndrome	DIS2IWS3	Strong	Genetic Variation	[3]
Immunodeficiency	DIS093I0	Strong	Biomarker	[7]
Keratoconus	DISOONXH	Strong	Biomarker	[8]
Major depressive disorder	DIS4CL3X	Strong	Genetic Variation	[9]
Polycystic ovarian syndrome	DISZ2BNG	Strong	Genetic Variation	[10]
Retinoblastoma	DISVPNPB	Strong	Biomarker	[11]
Vascular disease	DISVS67S	Strong	Genetic Variation	[12]
Age-related macular degeneration	DIS0XS2C	moderate	Genetic Variation	[13]
Ankylosing spondylitis	DISRC6IR	moderate	Genetic Variation	[14]
Asthma	DISW9QNS	moderate	Genetic Variation	[15]
Autoimmune disease	DISORMTM	moderate	Genetic Variation	[14]
Autoimmune disease, susceptibility to, 6	DISHNUXI	moderate	Genetic Variation	[14]
Autoimmune thyroid disease	DISIHC6A	moderate	Genetic Variation	[14]
Coeliac disease	DISIY60C	moderate	Genetic Variation	[14]
Common variable immunodeficiency	DISHE7JQ	moderate	Genetic Variation	[14]
Crohn disease	DIS2C5Q8	moderate	Genetic Variation	[14]
Hereditary macular dystrophy	DISEYSYY	moderate	Genetic Variation	[13]
Immune system disorder	DISAEGPH	moderate	Biomarker	[16]
Inherited retinal dystrophy	DISGGL77	moderate	CausalMutation	[17]
Juvenile idiopathic arthritis	DISQZGBV	moderate	Genetic Variation	[14]
Psoriasis	DIS59VMN	moderate	Genetic Variation	[14]
STAT3-related early-onset multisystem autoimmune disease	DISAXTN7	moderate	Genetic Variation	[14]
Systemic lupus erythematosus	DISI1SZ7	moderate	Genetic Variation	[14]
Type-1 diabetes	DIS7HLUB	moderate	Genetic Variation	[14]
Ulcerative colitis	DIS8K27O	moderate	Genetic Variation	[14]
Leber congenital amaurosis	DISMGH8F	Supportive	Autosomal dominant	[18]
Nanophthalmia	DISIULDO	Supportive	Autosomal dominant	[19]
Pigmented paravenous retinochoroidal atrophy	DISZG6IT	Supportive	Autosomal dominant	[20]
Retinitis pigmentosa	DISCGPY8	Supportive	Autosomal dominant	[21]
Stargardt disease	DISPXOTO	Disputed	Genetic Variation	[22]
Ciliopathy	DIS10G4I	Limited	Genetic Variation	[23]
Cone-rod dystrophy	DISY9RWN	Limited	Genetic Variation	[6]
Disorder of orbital region	DISH0ECJ	Limited	Biomarker	[24]
Microphthalmia	DISGEBES	Limited	Genetic Variation	[25]

5 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 crumbs homolog 1 (CRB1).	[26]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Protein crumbs homolog 1 (CRB1).	[27]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Protein crumbs homolog 1 (CRB1).	[28]
Belinostat	DM6OC53	Phase 2	Belinostat increases the expression of Protein crumbs homolog 1 (CRB1).	[28]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Protein crumbs homolog 1 (CRB1).	[29]

References

• [1] A G1103R mutation in CRB1 is co-inherited with high hyperopia and Leber congenital amaurosis. Ophthalmic Genet. 2006 Mar;27(1):15-20. doi: 10.1080/13816810500481840.
• [2] Genotypic and Phenotypic Characteristics of CRB1-Associated Retinal Dystrophies: A Long-Term Follow-up Study. Ophthalmology. 2017 Jun;124(6):884-895. doi: 10.1016/j.ophtha.2017.01.047. Epub 2017 Mar 21.
• [3] Infantile and childhood retinal blindness: a molecular perspective (The Franceschetti Lecture).Ophthalmic Genet. 2002 Jun;23(2):71-97. doi: 10.1076/opge.23.2.71.2214.
• [4] Whole exome sequencing using Ion Proton system enables reliable genetic diagnosis of inherited retinal dystrophies.Sci Rep. 2017 Feb 9;7:42078. doi: 10.1038/srep42078.
• [5] 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.
• [6] The correlation between CRB1 variants and the clinical severity of Brazilian patients with different inherited retinal dystrophy phenotypes.Sci Rep. 2017 Aug 17;7(1):8654. doi: 10.1038/s41598-017-09035-1.
• [7] Patient-specific iPSC-derived photoreceptor precursor cells as a means to investigate retinitis pigmentosa.Elife. 2013 Aug 27;2:e00824. doi: 10.7554/eLife.00824.
• [8] Leber Congenital Amaurosis.Adv Exp Med Biol. 2018;1085:131-137. doi: 10.1007/978-3-319-95046-4_26.
• [9] Genome-wide association study of depression phenotypes in UK Biobank identifies variants in excitatory synaptic pathways.Nat Commun. 2018 Apr 16;9(1):1470. doi: 10.1038/s41467-018-03819-3.
• [10] Genome-wide association of polycystic ovary syndrome implicates alterations in gonadotropin secretion in European ancestry populations.Nat Commun. 2015 Aug 18;6:7502. doi: 10.1038/ncomms8502.
• [11] A Meta-Analysis of Retinoblastoma Copy Numbers Refines the List of Possible Driver Genes Involved in Tumor Progression.PLoS One. 2016 Apr 26;11(4):e0153323. doi: 10.1371/journal.pone.0153323. eCollection 2016.
• [12] The severity of retinal pathology in homozygous Crb1rd8/rd8 mice is dependent on additional genetic factors.Hum Mol Genet. 2015 Jan 1;24(1):128-41. doi: 10.1093/hmg/ddu424. Epub 2014 Aug 21.
• [13] A clinical and molecular characterisation of CRB1-associated maculopathy.Eur J Hum Genet. 2018 May;26(5):687-694. doi: 10.1038/s41431-017-0082-2. Epub 2018 Feb 1.
• [14] Meta-analysis of shared genetic architecture across ten pediatric autoimmune diseases.Nat Med. 2015 Sep;21(9):1018-27. doi: 10.1038/nm.3933. Epub 2015 Aug 24.
• [15] Variants of DENND1B associated with asthma in children.N Engl J Med. 2010 Jan 7;362(1):36-44. doi: 10.1056/NEJMoa0901867. Epub 2009 Dec 23.
• [16] Controversial view of a genetically altered mouse model of focal retinal degeneration.Bioengineered. 2013 May-Jun;4(3):130-5. doi: 10.4161/bioe.22949. Epub 2012 Nov 29.
• [17] Molecular genetic analysis using targeted NGS analysis of 677 individuals with retinal dystrophy.Sci Rep. 2019 Feb 4;9(1):1219. doi: 10.1038/s41598-018-38007-2.
• [18] Review and update on the molecular basis of Leber congenital amaurosis. World J Clin Cases. 2015 Feb 16;3(2):112-24. doi: 10.12998/wjcc.v3.i2.112.
• [19] The spectrum of ocular phenotypes caused by mutations in the BEST1 gene. Prog Retin Eye Res. 2009 May;28(3):187-205. doi: 10.1016/j.preteyeres.2009.04.002. Epub 2009 Apr 16.
• [20] Pigmented paravenous chorioretinal atrophy is associated with a mutation within the crumbs homolog 1 (CRB1) gene. Invest Ophthalmol Vis Sci. 2005 Jan;46(1):322-8. doi: 10.1167/iovs.04-0734.
• [21] Nonsyndromic Retinitis Pigmentosa Overview. 2000 Aug 4 [updated 2023 Apr 6]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews(?) [Internet]. Seattle (WA): University of Washington, Seattle; 1993C2024.
• [22] Novel mutations in CRB1 and ABCA4 genes cause Leber congenital amaurosis and Stargardt disease in a Swedish family.Eur J Hum Genet. 2013 Nov;21(11):1266-71. doi: 10.1038/ejhg.2013.23. Epub 2013 Feb 27.
• [23] Whole exome sequencing as a diagnostic tool for patients with ciliopathy-like phenotypes.PLoS One. 2017 Aug 11;12(8):e0183081. doi: 10.1371/journal.pone.0183081. eCollection 2017.
• [24] 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.
• [25] CRB1: one gene, many phenotypes.Semin Ophthalmol. 2013 Sep-Nov;28(5-6):397-405. doi: 10.3109/08820538.2013.825277.
• [26] The neuroprotective action of the mood stabilizing drugs lithium chloride and sodium valproate is mediated through the up-regulation of the homeodomain protein Six1. Toxicol Appl Pharmacol. 2009 Feb 15;235(1):124-34.
• [27] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [28] 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.
• [29] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.