Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT1ZBDBV)

• DOT Name: Collagen alpha-2(IX) chain (COL9A2)
• Synonyms: Collagen alpha-2(IX) chain
• Gene Name: COL9A2
• Related Disease:
  Epiphyseal dysplasia, multiple, 2
  Metabolic disorder
  Nervous system disease
  Osteochondritis dissecans
  Stickler syndrome, type 5
  Alpha thalassemia
  Atrial fibrillation
  Bone osteosarcoma
  Cardiovascular disease
  Chronic kidney disease
  Depression
  Diastrophic dysplasia
  Dowling-Degos disease
  Familial hypercholesterolemia
  Familial Mediterranean fever
  Hemoglobin H disease
  Hypercholesterolemia, familial, 1
  Laurin-Sandrow syndrome
  Malignant soft tissue neoplasm
  Medulloblastoma
  Microscopic polyangiitis
  Multiple epiphyseal dysplasia
  Myopathy
  Neoplasm
  Non-insulin dependent diabetes
  Osteochondrodysplasia
  Osteosarcoma
  Pseudoachondroplasia
  Sarcoma
  Sciatica/lumbar radicular pain
  Spondyloepimetaphyseal dysplasia
  Triple negative breast cancer
  Connective tissue disorder
  High blood pressure
  Osteoarthritis
  Stickler syndrome type 1
  Multiple epiphyseal dysplasia due to collagen 9 anomaly
  Obsolete autosomal recessive Stickler syndrome
  Asthma
  Bone development disease
  Glioma
  Pancreatic ductal carcinoma
  Stickler syndrome
• UniProt ID: CO9A2_HUMAN
• PDB ID: 5CTD; 5CTI; 5CVA; 5CVB
• Pfam ID: PF01391
• Sequence:
  MAAATASPRSLLVLLQVVVLALAQIRGPPGERGPPGPPGPPGVPGSDGIDGDNGPPGKAG
  PPGPKGEPGKAGPDGPDGKPGIDGLTGAKGEPGPMGIPGVKGQPGLPGPPGLPGPGFAGP
  PGPPGPVGLPGEIGIRGPKGDPGPDGPSGPPGPPGKPGRPGTIQGLEGSADFLCPTNCPP
  GMKGPPGLQGVKGHAGKRGILGDPGHQGKPGPKGDVGASGEQGIPGPPGPQGIRGYPGMA
  GPKGETGPHGYKGMVGAIGATGPPGEEGPRGPPGRAGEKGDEGSPGIRGPQGITGPKGAT
  GPPGINGKDGTPGTPGMKGSAGQAGQPGSPGHQGLAGVPGQPGTKGGPGDQGEPGPQGLP
  GFSGPPGKEGEPGPRGEIGPQGIMGQKGDQGERGPVGQPGPQGRQGPKGEQGPPGIPGPQ
  GLPGVKGDKGSPGKTGPRGKVGDPGVAGLPGEKGEKGESGEPGPKGQQGVRGEPGYPGPS
  GDAGAPGVQGYPGPPGPRGLAGNRGVPGQPGRQGVEGRDATDQHIVDVALKMLQEQLAEV
  AVSAKREALGAVGMMGPPGPPGPPGYPGKQGPHGHPGPRGVPGIVGAVGQIGNTGPKGKR
  GEKGDPGEVGRGHPGMPGPPGIPGLPGRPGQAINGKDGDRGSPGAPGEAGRPGLPGPVGL
  PGFCEPAACLGASAYASARLTEPGSIKGP
• Function: Structural component of hyaline cartilage and vitreous of the eye.
• KEGG Pathway:
  PI3K-Akt sig.ling pathway (hsa04151)
  Focal adhesion (hsa04510)
  ECM-receptor interaction (hsa04512)
  Cytoskeleton in muscle cells (hsa04820)
  Protein digestion and absorption (hsa04974)
  Human papillomavirus infection (hsa05165)
• Reactome Pathway:
  Collagen biosynthesis and modifying enzymes (R-HSA-1650814)
  Signaling by PDGF (R-HSA-186797)
  Assembly of collagen fibrils and other multimeric structures (R-HSA-2022090)
  Integrin cell surface interactions (R-HSA-216083)
  ECM proteoglycans (R-HSA-3000178)
  NCAM1 interactions (R-HSA-419037)
  Collagen chain trimerization (R-HSA-8948216)
  Collagen degradation (R-HSA-1442490)

Molecular Interaction Atlas (MIA) of This DOT

43 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Epiphyseal dysplasia, multiple, 2	DISGRT1R	Definitive	Autosomal dominant	[1]
Metabolic disorder	DIS71G5H	Definitive	Biomarker	[2]
Nervous system disease	DISJ7GGT	Definitive	Genetic Variation	[3]
Osteochondritis dissecans	DIS1FGN4	Definitive	Genetic Variation	[4]
Stickler syndrome, type 5	DIS7JTG9	Definitive	Autosomal recessive	[5]
Alpha thalassemia	DIS5XGK0	Strong	Genetic Variation	[6]
Atrial fibrillation	DIS15W6U	Strong	Biomarker	[7]
Bone osteosarcoma	DIST1004	Strong	Altered Expression	[8]
Cardiovascular disease	DIS2IQDX	Strong	Biomarker	[9]
Chronic kidney disease	DISW82R7	Strong	Altered Expression	[10]
Depression	DIS3XJ69	Strong	Biomarker	[11]
Diastrophic dysplasia	DISNTGP7	Strong	Biomarker	[12]
Dowling-Degos disease	DISGTTEP	Strong	Genetic Variation	[13]
Familial hypercholesterolemia	DISC06IX	Strong	Genetic Variation	[2]
Familial Mediterranean fever	DISVP5WP	Strong	Genetic Variation	[14]
Hemoglobin H disease	DISHFWO5	Strong	Genetic Variation	[15]
Hypercholesterolemia, familial, 1	DISU411W	Strong	Biomarker	[16]
Laurin-Sandrow syndrome	DISOYBC3	Strong	Genetic Variation	[17]
Malignant soft tissue neoplasm	DISTC6NO	Strong	Altered Expression	[18]
Medulloblastoma	DISZD2ZL	Strong	Biomarker	[19]
Microscopic polyangiitis	DIS74KSO	Strong	Biomarker	[20]
Multiple epiphyseal dysplasia	DIS5FZLR	Strong	Biomarker	[21]
Myopathy	DISOWG27	Strong	Genetic Variation	[21]
Neoplasm	DISZKGEW	Strong	Biomarker	[22]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Genetic Variation	[9]
Osteochondrodysplasia	DIS9SPWW	Strong	Genetic Variation	[23]
Osteosarcoma	DISLQ7E2	Strong	Altered Expression	[8]
Pseudoachondroplasia	DISVJW4A	Strong	Genetic Variation	[24]
Sarcoma	DISZDG3U	Strong	Altered Expression	[18]
Sciatica/lumbar radicular pain	DIS01KTQ	Strong	Genetic Variation	[25]
Spondyloepimetaphyseal dysplasia	DISO4L5A	Strong	Biomarker	[26]
Triple negative breast cancer	DISAMG6N	Strong	Biomarker	[22]
Connective tissue disorder	DISKXBS3	moderate	Genetic Variation	[27]
High blood pressure	DISY2OHH	moderate	Biomarker	[28]
Osteoarthritis	DIS05URM	moderate	Genetic Variation	[29]
Stickler syndrome type 1	DIST5L4S	moderate	Genetic Variation	[30]
Multiple epiphyseal dysplasia due to collagen 9 anomaly	DISH640Y	Supportive	Autosomal dominant	[31]
Obsolete autosomal recessive Stickler syndrome	DISCSIL9	Supportive	Autosomal recessive	[5]
Asthma	DISW9QNS	Limited	Biomarker	[32]
Bone development disease	DISVKAZS	Limited	Biomarker	[33]
Glioma	DIS5RPEH	Limited	Biomarker	[34]
Pancreatic ductal carcinoma	DIS26F9Q	Limited	Genetic Variation	[35]
Stickler syndrome	DISQWFHN	Limited	Autosomal recessive	[36]

8 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 Collagen alpha-2(IX) chain (COL9A2).	[37]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Collagen alpha-2(IX) chain (COL9A2).	[38]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Collagen alpha-2(IX) chain (COL9A2).	[39]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Collagen alpha-2(IX) chain (COL9A2).	[40]
Arsenic	DMTL2Y1	Approved	Arsenic increases the expression of Collagen alpha-2(IX) chain (COL9A2).	[41]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Collagen alpha-2(IX) chain (COL9A2).	[42]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Collagen alpha-2(IX) chain (COL9A2).	[43]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Collagen alpha-2(IX) chain (COL9A2).	[44]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Collagen alpha-2(IX) chain (COL9A2).	[45]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Collagen alpha-2(IX) chain (COL9A2).	[46]

References

• [1] Identification of novel pro-alpha2(IX) collagen gene mutations in two families with distinctive oligo-epiphyseal forms of multiple epiphyseal dysplasia. Am J Hum Genet. 1999 Jul;65(1):31-8. doi: 10.1086/302440.
• [2] Diagnosis of families with familial hypercholesterolaemia and/or Apo B-100 defect by means of DNA analysis of LDL-receptor gene mutations.J Inherit Metab Dis. 2007 Apr;30(2):239-47. doi: 10.1007/s10545-007-0563-5. Epub 2007 Mar 8.
• [3] MED23 mutation links intellectual disability to dysregulation of immediate early gene expression. Science. 2011 Aug 26;333(6046):1161-3. doi: 10.1126/science.1206638.
• [4] A suspected genetic form of bilateral osteochondritis dissecans of the knee in a Dutch family.Knee. 2015 Dec;22(6):677-82. doi: 10.1016/j.knee.2015.05.004. Epub 2015 Jun 27.
• [5] A loss of function mutation in the COL9A2 gene causes autosomal recessive Stickler syndrome. Am J Med Genet A. 2011 Jul;155A(7):1668-72. doi: 10.1002/ajmg.a.34071. Epub 2011 Jun 10.
• [6] Identification of -globin chain variants: a report from Iran.Arch Iran Med. 2012 Sep;15(9):564-7.
• [7] Prevalence and Incidence of Atrial Fibrillation in the General Population Based on National Health Insurance Special Health Checkups- TAMA MED Project-AF.Circ J. 2019 Feb 25;83(3):524-531. doi: 10.1253/circj.CJ-18-1038. Epub 2019 Jan 11.
• [8] Gene expression profile of the whole Mediator complex in human osteosarcoma and normal osteoblasts.Med Oncol. 2013 Dec;30(4):739. doi: 10.1007/s12032-013-0739-9. Epub 2013 Oct 8.
• [9] BARI 2D: A Reanalysis Focusing on Cardiovascular Events.Mayo Clin Proc. 2019 Nov;94(11):2249-2262. doi: 10.1016/j.mayocp.2019.04.015. Epub 2019 Oct 4.
• [10] Serum protease activity in chronic kidney disease patients: The GANI_MED renal cohort.Exp Biol Med (Maywood). 2017 Mar;242(5):554-563. doi: 10.1177/1535370216684040. Epub 2016 Dec 30.
• [11] Can targeted metabolomics predict depression recovery? Results from the CO-MED trial.Transl Psychiatry. 2019 Jan 16;9(1):11. doi: 10.1038/s41398-018-0349-6.
• [12] A compound heterozygote of novel and recurrent DTDST mutations results in a novel intermediate phenotype of Desbuquois dysplasia, diastrophic dysplasia, and recessive form of multiple epiphyseal dysplasia.J Hum Genet. 2008;53(8):764-768. doi: 10.1007/s10038-008-0305-z. Epub 2008 Jun 14.
• [13] MRI Phenotyping of COL9A2/Trp2 and COL9A3/Trp3 Alleles in Lumbar Disc Disease: A Case-control Study in South-Western Iranian Population Reveals a Significant Trp3-Disease Association in Males.Spine (Phila Pa 1976). 2016 Nov 1;41(21):1661-1667. doi: 10.1097/BRS.0000000000001617.
• [14] Phenotype-genotype correlation in Jewish patients suffering from familial Mediterranean fever (FMF).Eur J Hum Genet. 1998 Jan;6(1):95-7. doi: 10.1038/sj.ejhg.5200170.
• [15] HbH disease associated with the (--MED) deletion in a Brazilian black woman.Acta Haematol. 1992;87(3):145-7. doi: 10.1159/000204741.
• [16] Genetic diagnosis of familial hypercholesterolemia in affected relatives using pedigree tracing.Clin Biochem. 1996 Aug;29(4):371-7. doi: 10.1016/0009-9120(96)00017-3.
• [17] A haplotype at the COL9A2 gene locus contributes to the genetic risk for lumbar spinal stenosis in the Korean population.Spine (Phila Pa 1976). 2011 Jul 15;36(16):1273-8. doi: 10.1097/BRS.0b013e31820e6282.
• [18] S-MED: sarcoma microRNA expression database.Lab Invest. 2010 May;90(5):753-61. doi: 10.1038/labinvest.2010.53. Epub 2010 Mar 8.
• [19] miR-219 inhibits the proliferation, migration and invasion of medulloblastoma cells by targeting CD164.Int J Mol Med. 2014 Jul;34(1):237-43. doi: 10.3892/ijmm.2014.1749. Epub 2014 Apr 22.
• [20] Prediction of response to remission induction therapy by gene expression profiling of peripheral blood in Japanese patients with microscopic polyangiitis.Arthritis Res Ther. 2017 May 31;19(1):117. doi: 10.1186/s13075-017-1328-7.
• [21] Type IX collagen gene mutations can result in multiple epiphyseal dysplasia that is associated with osteochondritis dissecans and a mild myopathy.Am J Med Genet A. 2010 Apr;152A(4):863-9. doi: 10.1002/ajmg.a.33240.
• [22] Pathological expression of tissue factor confers promising antitumor response to a novel therapeutic antibody SC1 in triple negative breast cancer and pancreatic adenocarcinoma.Oncotarget. 2017 Jul 10;8(35):59086-59102. doi: 10.18632/oncotarget.19175. eCollection 2017 Aug 29.
• [23] Intrafamilial phenotypic diversity in multiple epiphyseal dysplasia associated with a COL9A2 mutation (EDM2).Clin Rheumatol. 2006 Jul;25(4):591-5. doi: 10.1007/s10067-005-0034-z. Epub 2006 Jan 27.
• [24] Pseudoachondroplasia and multiple epiphyseal dysplasia: a 7-year comprehensive analysis of the known disease genes identify novel and recurrent mutations and provides an accurate assessment of their relative contribution.Hum Mutat. 2012 Jan;33(1):144-57. doi: 10.1002/humu.21611. Epub 2011 Oct 31.
• [25] Intervertebral disc degeneration in relation to the COL9A3 and the IL-1ss gene polymorphisms.Eur Spine J. 2006 May;15(5):613-9. doi: 10.1007/s00586-005-0988-1. Epub 2005 Aug 17.
• [26] Linkage studies of a Missouri kindred with autosomal dominant spondyloepimetaphyseal dysplasia (SEMD) indicate genetic heterogeneity.J Bone Miner Res. 1997 Aug;12(8):1204-9. doi: 10.1359/jbmr.1997.12.8.1204.
• [27] Candidate gene association study of magnetic resonance imaging-based hip osteoarthritis (OA): evidence for COL9A2 gene as a common predisposing factor for hip OA and lumbar disc degeneration.J Rheumatol. 2011 Apr;38(4):747-52. doi: 10.3899/jrheum.100080. Epub 2010 Dec 15.
• [28] Modulation of Sympathetic Overactivity to Treat Resistant Hypertension.Curr Hypertens Rep. 2018 Sep 7;20(11):92. doi: 10.1007/s11906-018-0893-8.
• [29] A matrilin-3 mutation associated with osteoarthritis does not affect collagen affinity but promotes the formation of wider cartilage collagen fibrils.Hum Mutat. 2010 Mar;31(3):254-63. doi: 10.1002/humu.21182.
• [30] Alternative splicing modifies the effect of mutations in COL11A1 and results in recessive type 2 Stickler syndrome with profound hearing loss. J Med Genet. 2013 Nov;50(11):765-71. doi: 10.1136/jmedgenet-2012-101499. Epub 2013 Aug 6.
• [31] Multiple Epiphyseal Dysplasia, Autosomal Dominant. 2003 Jan 8 [updated 2019 Apr 25]. 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.
• [32] Clinical efficacy of implementing Bio Immune(G)ene MEDicine in the treatment of chronic asthma with the objective of reducing or removing effectively corticosteroid therapy: A novel approach and promising results.Exp Ther Med. 2018 Jun;15(6):5133-5140. doi: 10.3892/etm.2018.6019. Epub 2018 Apr 2.
• [33] Multilayered patella: similar radiographic findings in pseudoachondroplasia and recessive multiple epiphyseal dysplasia.Am J Med Genet A. 2008 Jul 1;146A(13):1682-6. doi: 10.1002/ajmg.a.32313.
• [34] Therapeutic efficacy of vinorelbine against pediatric and adult central nervous system tumors.Cancer Chemother Pharmacol. 1998;42(6):479-82. doi: 10.1007/s002800050848.
• [35] Multiplex Enrichment and Detection of Rare KRAS Mutations in Liquid Biopsy Samples using Digital Droplet Pre-Amplification.Anal Chem. 2019 Jun 18;91(12):7516-7523. doi: 10.1021/acs.analchem.8b01605. Epub 2019 May 24.
• [36] 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.
• [37] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [38] 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.
• [39] Benzodithiophenes potentiate differentiation of acute promyelocytic leukemia cells by lowering the threshold for ligand-mediated corepressor/coactivator exchange with retinoic acid receptor alpha and enhancing changes in all-trans-retinoic acid-regulated gene expression. Cancer Res. 2005 Sep 1;65(17):7856-65. doi: 10.1158/0008-5472.CAN-05-1056.
• [40] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [41] Inorganic arsenic exposure promotes malignant progression by HDAC6-mediated down-regulation of HTRA1. J Appl Toxicol. 2023 Aug;43(8):1214-1224. doi: 10.1002/jat.4457. Epub 2023 Mar 11.
• [42] 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.
• [43] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [44] 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.
• [45] 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.
• [46] 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.