Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTASWJ69)

• DOT Name: Collagen alpha-2(VIII) chain (COL8A2)
• Synonyms: Endothelial collagen
• Gene Name: COL8A2
• Related Disease:
  Congenital hereditary endothelial dystrophy of cornea
  Corneal dystrophy
  Corneal dystrophy, Fuchs endothelial, 1
  Diabetic kidney disease
  Fleck corneal dystrophy
  Focal segmental glomerulosclerosis
  Hepatocellular carcinoma
  Keratoconus
  Megalocornea
  OPTN-related open angle glaucoma
  Posterior polymorphous corneal dystrophy 2
  Retinopathy
  Fuchs' endothelial dystrophy
  Posterior polymorphous corneal dystrophy
  Connective tissue disorder
  Eosinophilic esophagitis
  Fish eye disease
  Glaucoma/ocular hypertension
  Posterior polymorphous corneal dystrophy 1
• UniProt ID: CO8A2_HUMAN
• Pfam ID: PF00386 ; PF01391
• Sequence:
  MLGTLTPLSSLLLLLLVLVLGCGPRASSGGGAGGAAGYAPVKYIQPMQKGPVGPPFREGK
  GQYLEMPLPLLPMDLKGEPGPPGKPGPRGPPGPPGFPGKPGMGKPGLHGQPGPAGPPGFS
  RMGKAGPPGLPGKVGPPGQPGLRGEPGIRGDQGLRGPPGPPGLPGPSGITIPGKPGAQGV
  PGPPGFQGEPGPQGEPGPPGDRGLKGDNGVGQPGLPGAPGQGGAPGPPGLPGPAGLGKPG
  LDGLPGAPGDKGESGPPGVPGPRGEPGAVGPKGPPGVDGVGVPGAAGLPGPQGPSGAKGE
  PGTRGPPGLIGPTGYGMPGLPGPKGDRGPAGVPGLLGDRGEPGEDGEPGEQGPQGLGGPP
  GLPGSAGLPGRRGPPGPKGEAGPGGPPGVPGIRGDQGPSGLAGKPGVPGERGLPGAHGPP
  GPTGPKGEPGFTGRPGGPGVAGALGQKGDLGLPGQPGLRGPSGIPGLQGPAGPIGPQGLP
  GLKGEPGLPGPPGEGRAGEPGTAGPTGPPGVPGSPGITGPPGPPGPPGPPGAPGAFDETG
  IAGLHLPNGGVEGAVLGKGGKPQFGLGELSAHATPAFTAVLTSPFPASGMPVKFDRTLYN
  GHSGYNPATGIFTCPVGGVYYFAYHVHVKGTNVWVALYKNNVPATYTYDEYKKGYLDQAS
  GGAVLQLRPNDQVWVQMPSDQANGLYSTEYIHSSFSGFLLCPT
• Function: Macromolecular component of the subendothelium. Major component of the Descemet's membrane (basement membrane) of corneal endothelial cells. Also a component of the endothelia of blood vessels. Necessary for migration and proliferation of vascular smooth muscle cells and thus, has a potential role in the maintenance of vessel wall integrity and structure, in particular in atherogenesis.
• Tissue Specificity: Expressed primarily in the subendothelium of large blood vessels. Also expressed in arterioles and venules in muscle, heart, kidney, spleen, umbilical cord, liver and lung and is also found in connective tissue layers around hair follicles, around nerve bundles in muscle, in the dura of the optic nerve, in cornea and sclera, and in the perichondrium of cartilaginous tissues. In the kidney, expressed in mesangial cells, glomerular endothelial cells, and tubular epithelial cells. Also expressed in mast cells, and in astrocytes during the repair process. Expressed in Descemet's membrane.
• KEGG Pathway: Protein digestion and absorption (hsa04974)
• Reactome Pathway:
  Collagen biosynthesis and modifying enzymes (R-HSA-1650814)
  Assembly of collagen fibrils and other multimeric structures (R-HSA-2022090)
  Integrin cell surface interactions (R-HSA-216083)
  Collagen chain trimerization (R-HSA-8948216)
  Collagen degradation (R-HSA-1442490)

Molecular Interaction Atlas (MIA) of This DOT

19 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Congenital hereditary endothelial dystrophy of cornea	DISHLPKQ	Strong	Genetic Variation	[1]
Corneal dystrophy	DISRDPA6	Strong	Genetic Variation	[2]
Corneal dystrophy, Fuchs endothelial, 1	DISOQIO0	Strong	Autosomal dominant	[3]
Diabetic kidney disease	DISJMWEY	Strong	Altered Expression	[4]
Fleck corneal dystrophy	DISERQJ1	Strong	Biomarker	[5]
Focal segmental glomerulosclerosis	DISJNHH0	Strong	Altered Expression	[4]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[6]
Keratoconus	DISOONXH	Strong	Genetic Variation	[7]
Megalocornea	DISIMNF0	Strong	Biomarker	[8]
OPTN-related open angle glaucoma	DISDR98A	Strong	Genetic Variation	[9]
Posterior polymorphous corneal dystrophy 2	DISCCI5U	Strong	Autosomal dominant	[1]
Retinopathy	DISB4B0F	moderate	Genetic Variation	[10]
Fuchs' endothelial dystrophy	DISL7TXC	Supportive	Autosomal dominant	[11]
Posterior polymorphous corneal dystrophy	DISHAYH6	Supportive	Autosomal dominant	[1]
Connective tissue disorder	DISKXBS3	Limited	Biomarker	[12]
Eosinophilic esophagitis	DISR8WSB	Limited	Biomarker	[12]
Fish eye disease	DISYTZNQ	Limited	Genetic Variation	[13]
Glaucoma/ocular hypertension	DISLBXBY	Limited	Biomarker	[14]
Posterior polymorphous corneal dystrophy 1	DISVGA4Z	Limited	Genetic Variation	[15]

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 Collagen alpha-2(VIII) chain (COL8A2).	[16]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Collagen alpha-2(VIII) chain (COL8A2).	[24]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Collagen alpha-2(VIII) chain (COL8A2).	[17]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Collagen alpha-2(VIII) chain (COL8A2).	[18]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Collagen alpha-2(VIII) chain (COL8A2).	[19]
Decitabine	DMQL8XJ	Approved	Decitabine increases the expression of Collagen alpha-2(VIII) chain (COL8A2).	[20]
Progesterone	DMUY35B	Approved	Progesterone decreases the expression of Collagen alpha-2(VIII) chain (COL8A2).	[21]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of Collagen alpha-2(VIII) chain (COL8A2).	[17]
Alitretinoin	DMME8LH	Approved	Alitretinoin increases the expression of Collagen alpha-2(VIII) chain (COL8A2).	[17]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Collagen alpha-2(VIII) chain (COL8A2).	[22]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone increases the expression of Collagen alpha-2(VIII) chain (COL8A2).	[23]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Collagen alpha-2(VIII) chain (COL8A2).	[25]
all-trans-4-oxo-retinoic acid	DMM2R1N	Investigative	all-trans-4-oxo-retinoic acid decreases the expression of Collagen alpha-2(VIII) chain (COL8A2).	[17]

References

• [1] Missense mutations in COL8A2, the gene encoding the alpha2 chain of type VIII collagen, cause two forms of corneal endothelial dystrophy. Hum Mol Genet. 2001 Oct 1;10(21):2415-23. doi: 10.1093/hmg/10.21.2415.
• [2] Distinct Clinical Phenotype of Corneal Dystrophy Predicts the p.(Leu450Trp) Substitution in COL8A2.Cornea. 2016 May;35(5):587-91. doi: 10.1097/ICO.0000000000000796.
• [3] British family with early-onset Fuchs' endothelial corneal dystrophy associated with p.L450W mutation in the COL8A2 gene. Br J Ophthalmol. 2007 Dec;91(12):1717-8. doi: 10.1136/bjo.2007.115154.
• [4] Collagen type VIII expression in human diabetic nephropathy.Eur J Clin Invest. 2007 Oct;37(10):767-73. doi: 10.1111/j.1365-2362.2007.01864.x.
• [5] Inheritance of a novel COL8A2 mutation defines a distinct early-onset subtype of fuchs corneal dystrophy.Invest Ophthalmol Vis Sci. 2005 Jun;46(6):1934-9. doi: 10.1167/iovs.04-0937.
• [6] All-trans retinoic acid protects hepatocellular carcinoma cells against serum-starvation-induced cell death by upregulating collagen 8A2.FEBS J. 2013 Mar;280(5):1308-19. doi: 10.1111/febs.12122. Epub 2013 Feb 6.
• [7] Mutational spectrum of the ZEB1 gene in corneal dystrophies supports a genotype-phenotype correlation.Invest Ophthalmol Vis Sci. 2013 May 3;54(5):3215-23. doi: 10.1167/iovs.13-11781.
• [8] Keratoconus is not associated with mutations in COL8A1 and COL8A2.Cornea. 2007 Sep;26(8):963-5. doi: 10.1097/ICO.0b013e31811dfaf7.
• [9] The genetics of POAG in black South Africans: a candidate gene association study.Sci Rep. 2015 Feb 11;5:8378. doi: 10.1038/srep08378.
• [10] Diabetes duration may modify the association between genetic variation in the glycoprotein Ia subunit of the platelet collagen receptor and risk of severe diabetic retinopathy: a working hypothesis.Thromb Haemost. 2003 Jan;89(1):142-8.
• [11] Q455V mutation in COL8A2 is associated with Fuchs' corneal dystrophy in Korean patients. Eye (Lond). 2009 Apr;23(4):895-903. doi: 10.1038/eye.2008.116. Epub 2008 May 9.
• [12] High prevalence of eosinophilic esophagitis in patients with inherited connective tissue disorders.J Allergy Clin Immunol. 2013 Aug;132(2):378-86. doi: 10.1016/j.jaci.2013.02.030. Epub 2013 Apr 19.
• [13] Association of TCF4 and CLU polymorphisms with Fuchs' endothelial dystrophy and implication of CLU and TGFBI proteins in the disease process.Eur J Hum Genet. 2012 Jun;20(6):632-8. doi: 10.1038/ejhg.2011.248. Epub 2012 Jan 11.
• [14] Distribution of COL8A2 and COL8A1 gene variants in Caucasian primary open angle glaucoma patients with thin central corneal thickness.Mol Vis. 2010 Oct 29;16:2185-91.
• [15] No pathogenic mutations identified in the COL8A2 gene or four positional candidate genes in patients with posterior polymorphous corneal dystrophy.Invest Ophthalmol Vis Sci. 2005 May;46(5):1599-603. doi: 10.1167/iovs.04-1321.
• [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] Retinoic acid and its 4-oxo metabolites are functionally active in human skin cells in vitro. J Invest Dermatol. 2005 Jul;125(1):143-53.
• [18] Global effects of inorganic arsenic on gene expression profile in human macrophages. Mol Immunol. 2009 Feb;46(4):649-56.
• [19] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [20] Characterization of DOK1, a candidate tumor suppressor gene, in epithelial ovarian cancer. Mol Oncol. 2011 Oct;5(5):438-53. doi: 10.1016/j.molonc.2011.07.003. Epub 2011 Jul 26.
• [21] Coordinate up-regulation of TMEM97 and cholesterol biosynthesis genes in normal ovarian surface epithelial cells treated with progesterone: implications for pathogenesis of ovarian cancer. BMC Cancer. 2007 Dec 11;7:223.
• [22] 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.
• [23] Identification by automated screening of a small molecule that selectively eliminates neural stem cells derived from hESCs but not dopamine neurons. PLoS One. 2009 Sep 23;4(9):e7155.
• [24] 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.
• [25] Regulation of chromatin assembly and cell transformation by formaldehyde exposure in human cells. Environ Health Perspect. 2017 Sep 21;125(9):097019.