Details of Drug Off-Target (DOT)

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

• DOT Name: Collagen alpha-3(IX) chain (COL9A3)
• Synonyms: Collagen alpha-3(IX) chain
• Gene Name: COL9A3
• Related Disease:
  Epiphyseal dysplasia, multiple, 3
  Metabolic disorder
  Nervous system disease
  Primary biliary cholangitis
  Stickler syndrome
  Stickler syndrome, IIa 6
  Alpha thalassemia
  Atrial fibrillation
  Autism spectrum disorder
  Autoimmune disease
  Bone osteosarcoma
  Cardiovascular disease
  Cervix disorder
  Chronic kidney disease
  Connective tissue disorder
  Deafness
  Depression
  Diastrophic dysplasia
  Dowling-Degos disease
  Familial hypercholesterolemia
  Familial Mediterranean fever
  Hemoglobin H disease
  Hypercholesterolemia, familial, 1
  Malignant soft tissue neoplasm
  Medulloblastoma
  Non-insulin dependent diabetes
  Obesity
  Osteoarthritis
  Osteoporosis
  Osteosarcoma
  Pseudoachondroplasia
  Sarcoma
  Spondyloepimetaphyseal dysplasia
  Stickler syndrome type 1
  Triple negative breast cancer
  High blood pressure
  Melanoma
  Neoplasm
  Multiple epiphyseal dysplasia due to collagen 9 anomaly
  Obsolete autosomal recessive Stickler syndrome
  Asthma
  Bipolar disorder
  Bone development disease
  Glioma
  Neurodevelopmental disorder
  Pancreatic ductal carcinoma
  Schizophrenia
  Type-1/2 diabetes
• UniProt ID: CO9A3_HUMAN
• PDB ID: 5CTD; 5CTI; 5CVA; 5CVB
• Pfam ID: PF01391
• Sequence:
  MAGPRACAPLLLLLLLGELLAAAGAQRVGLPGPPGPPGPPGKPGQDGIDGEAGPPGLPGP
  PGPKGAPGKPGKPGEAGLPGLPGVDGLTGRDGPPGPKGAPGERGSLGPPGPPGLGGKGLP
  GPPGEAGVSGPPGGIGLRGPPGPSGLPGLPGPPGPPGPPGHPGVLPEGATDLQCPSICPP
  GPPGPPGMPGFKGPTGYKGEQGEVGKDGEKGDPGPPGPAGLPGSVGLQGPRGLRGLPGPL
  GPPGDRGPIGFRGPPGIPGAPGKAGDRGERGPEGFRGPKGDLGRPGPKGTPGVAGPSGEP
  GMPGKDGQNGVPGLDGQKGEAGRNGAPGEKGPNGLPGLPGRAGSKGEKGERGRAGELGEA
  GPSGEPGVPGDAGMPGERGEAGHRGSAGALGPQGPPGAPGVRGFQGQKGSMGDPGLPGPQ
  GLRGDVGDRGPGGAAGPKGDQGIAGSDGLPGDKGELGPSGLVGPKGESGSRGELGPKGTQ
  GPNGTSGVQGVPGPPGPLGLQGVPGVPGITGKPGVPGKEASEQRIRELCGGMISEQIAQL
  AAHLRKPLAPGSIGRPGPAGPPGPPGPPGSIGHPGARGPPGYRGPTGELGDPGPRGNQGD
  RGDKGAAGAGLDGPEGDQGPQGPQGVPGTSKDGQDGAPGEPGPPGDPGLPGAIGAQGTPG
  ICDTSACQGAVLGGVGEKSGSRSS
• 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

48 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Epiphyseal dysplasia, multiple, 3	DISKEN43	Definitive	Autosomal dominant	[1]
Metabolic disorder	DIS71G5H	Definitive	Biomarker	[2]
Nervous system disease	DISJ7GGT	Definitive	Genetic Variation	[3]
Primary biliary cholangitis	DIS43E0O	Definitive	Biomarker	[4]
Stickler syndrome	DISQWFHN	Definitive	Autosomal recessive	[5]
Stickler syndrome, IIa 6	DISJ7NYA	Definitive	Autosomal recessive	[6]
Alpha thalassemia	DIS5XGK0	Strong	Genetic Variation	[7]
Atrial fibrillation	DIS15W6U	Strong	Biomarker	[8]
Autism spectrum disorder	DISXK8NV	Strong	Biomarker	[9]
Autoimmune disease	DISORMTM	Strong	Biomarker	[10]
Bone osteosarcoma	DIST1004	Strong	Altered Expression	[11]
Cardiovascular disease	DIS2IQDX	Strong	Biomarker	[12]
Cervix disorder	DIS1HG31	Strong	Biomarker	[13]
Chronic kidney disease	DISW82R7	Strong	Altered Expression	[14]
Connective tissue disorder	DISKXBS3	Strong	Biomarker	[1]
Deafness	DISKCLH4	Strong	Genetic Variation	[15]
Depression	DIS3XJ69	Strong	Biomarker	[16]
Diastrophic dysplasia	DISNTGP7	Strong	Biomarker	[17]
Dowling-Degos disease	DISGTTEP	Strong	Genetic Variation	[18]
Familial hypercholesterolemia	DISC06IX	Strong	Genetic Variation	[2]
Familial Mediterranean fever	DISVP5WP	Strong	Genetic Variation	[19]
Hemoglobin H disease	DISHFWO5	Strong	Genetic Variation	[20]
Hypercholesterolemia, familial, 1	DISU411W	Strong	Biomarker	[21]
Malignant soft tissue neoplasm	DISTC6NO	Strong	Altered Expression	[22]
Medulloblastoma	DISZD2ZL	Strong	Biomarker	[23]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Genetic Variation	[12]
Obesity	DIS47Y1K	Strong	Genetic Variation	[24]
Osteoarthritis	DIS05URM	Strong	Genetic Variation	[25]
Osteoporosis	DISF2JE0	Strong	Biomarker	[26]
Osteosarcoma	DISLQ7E2	Strong	Altered Expression	[11]
Pseudoachondroplasia	DISVJW4A	Strong	Genetic Variation	[27]
Sarcoma	DISZDG3U	Strong	Altered Expression	[22]
Spondyloepimetaphyseal dysplasia	DISO4L5A	Strong	Biomarker	[28]
Stickler syndrome type 1	DIST5L4S	Strong	Genetic Variation	[29]
Triple negative breast cancer	DISAMG6N	Strong	Biomarker	[30]
High blood pressure	DISY2OHH	moderate	Biomarker	[31]
Melanoma	DIS1RRCY	moderate	Altered Expression	[32]
Neoplasm	DISZKGEW	moderate	Biomarker	[30]
Multiple epiphyseal dysplasia due to collagen 9 anomaly	DISH640Y	Supportive	Autosomal dominant	[33]
Obsolete autosomal recessive Stickler syndrome	DISCSIL9	Supportive	Autosomal recessive	[34]
Asthma	DISW9QNS	Limited	Biomarker	[35]
Bipolar disorder	DISAM7J2	Limited	Biomarker	[36]
Bone development disease	DISVKAZS	Limited	Biomarker	[37]
Glioma	DIS5RPEH	Limited	Biomarker	[38]
Neurodevelopmental disorder	DIS372XH	Limited	Biomarker	[36]
Pancreatic ductal carcinoma	DIS26F9Q	Limited	Genetic Variation	[39]
Schizophrenia	DISSRV2N	Limited	Genetic Variation	[36]
Type-1/2 diabetes	DISIUHAP	Limited	Biomarker	[40]

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Etoposide	DMNH3PG	Approved	Collagen alpha-3(IX) chain (COL9A3) affects the response to substance of Etoposide.	[51]
Mitomycin	DMH0ZJE	Approved	Collagen alpha-3(IX) chain (COL9A3) affects the response to substance of Mitomycin.	[51]

1 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-3(IX) chain (COL9A3).	[41]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Collagen alpha-3(IX) chain (COL9A3).	[42]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Collagen alpha-3(IX) chain (COL9A3).	[43]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Collagen alpha-3(IX) chain (COL9A3).	[44]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Collagen alpha-3(IX) chain (COL9A3).	[45]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Collagen alpha-3(IX) chain (COL9A3).	[46]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Collagen alpha-3(IX) chain (COL9A3).	[46]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Collagen alpha-3(IX) chain (COL9A3).	[47]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of Collagen alpha-3(IX) chain (COL9A3).	[48]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Collagen alpha-3(IX) chain (COL9A3).	[49]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of Collagen alpha-3(IX) chain (COL9A3).	[50]

References

• [1] Novel COL9A3 mutation in a family with multiple epiphyseal dysplasia. Am J Med Genet A. 2005 Jan 15;132A(2):181-4. doi: 10.1002/ajmg.a.30411.
• [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] CD8 T cells mediate direct biliary ductule damage in nonobese diabetic autoimmune biliary disease.J Immunol. 2011 Jan 15;186(2):1259-67. doi: 10.4049/jimmunol.1001597. Epub 2010 Dec 17.
• [5] 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.
• [6] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [7] Identification of -globin chain variants: a report from Iran.Arch Iran Med. 2012 Sep;15(9):564-7.
• [8] 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.
• [9] Young children who screen positive for autism: Stability, change and "comorbidity" over two years.Res Dev Disabil. 2018 Jan;72:297-307. doi: 10.1016/j.ridd.2016.10.004. Epub 2016 Nov 3.
• [10] Genetic control of autoimmune diabetes in the NOD mouse.Annu Rev Immunol. 1995;13:179-200. doi: 10.1146/annurev.iy.13.040195.001143.
• [11] 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.
• [12] 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.
• [13] Current practice and usual care of major cervical disorders in Korea: A cross-sectional study of Korean health insurance review and assessment service national patient sample data.Medicine (Baltimore). 2017 Nov;96(46):e8751. doi: 10.1097/MD.0000000000008751.
• [14] 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.
• [15] Mutation analysis of COL9A3, a gene highly expressed in the cochlea, in hearing loss patients.Auris Nasus Larynx. 2005 Jun;32(2):113-7. doi: 10.1016/j.anl.2005.01.011. Epub 2005 Mar 24.
• [16] 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.
• [17] 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.
• [18] 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.
• [19] 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.
• [20] HbH disease associated with the (--MED) deletion in a Brazilian black woman.Acta Haematol. 1992;87(3):145-7. doi: 10.1159/000204741.
• [21] 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.
• [22] S-MED: sarcoma microRNA expression database.Lab Invest. 2010 May;90(5):753-61. doi: 10.1038/labinvest.2010.53. Epub 2010 Mar 8.
• [23] 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.
• [24] COL9A3 gene polymorphism and obesity in intervertebral disc degeneration of the lumbar spine: evidence of gene-environment interaction.Spine (Phila Pa 1976). 2002 Dec 1;27(23):2691-6. doi: 10.1097/00007632-200212010-00008.
• [25] 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.
• [26] Low-trauma fractures and bone mineral density testing in adults with and without intellectual and developmental disabilities: a population study.Osteoporos Int. 2017 Feb;28(2):727-732. doi: 10.1007/s00198-016-3740-2. Epub 2016 Sep 9.
• [27] 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.
• [28] 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.
• [29] LOXL3 novel mutation causing a rare form of autosomal recessive Stickler syndrome. Clin Genet. 2019 Feb;95(2):325-328. doi: 10.1111/cge.13465. Epub 2018 Nov 18.
• [30] 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.
• [31] Modulation of Sympathetic Overactivity to Treat Resistant Hypertension.Curr Hypertens Rep. 2018 Sep 7;20(11):92. doi: 10.1007/s11906-018-0893-8.
• [32] Diagnostic SOX10 gene signatures in salivary adenoid cystic and breast basal-like carcinomas.Br J Cancer. 2013 Jul 23;109(2):444-51. doi: 10.1038/bjc.2013.326. Epub 2013 Jun 25.
• [33] 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.
• [34] Autosomal recessive Stickler syndrome due to a loss of function mutation in the COL9A3 gene. Am J Med Genet A. 2014 Jan;164A(1):42-7. doi: 10.1002/ajmg.a.36165. Epub 2013 Nov 22.
• [35] 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.
• [36] Modeling the neuropsychiatric manifestations of Lowe syndrome using induced pluripotent stem cells: defective F-actin polymerization and WAVE-1 expression in neuronal cells.Mol Autism. 2018 Aug 15;9:44. doi: 10.1186/s13229-018-0227-3. eCollection 2018.
• [37] 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.
• [38] Therapeutic efficacy of vinorelbine against pediatric and adult central nervous system tumors.Cancer Chemother Pharmacol. 1998;42(6):479-82. doi: 10.1007/s002800050848.
• [39] 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.
• [40] A new indanedione derivative alleviates symptoms of diabetes by modulating RAGE-NF-kappaB pathway in db/db mice.Biochem Biophys Res Commun. 2018 Jul 2;501(4):863-870. doi: 10.1016/j.bbrc.2018.05.043. Epub 2018 May 21.
• [41] 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.
• [42] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [43] 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.
• [44] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [45] 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.
• [46] 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.
• [47] 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.
• [48] Comprehensive analysis of transcriptomic changes induced by low and high doses of bisphenol A in HepG2 spheroids in vitro and rat liver in vivo. Environ Res. 2019 Jun;173:124-134. doi: 10.1016/j.envres.2019.03.035. Epub 2019 Mar 18.
• [49] 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.
• [50] Transcriptome and DNA methylation changes modulated by sulforaphane induce cell cycle arrest, apoptosis, DNA damage, and suppression of proliferation in human liver cancer cells. Food Chem Toxicol. 2020 Feb;136:111047. doi: 10.1016/j.fct.2019.111047. Epub 2019 Dec 12.
• [51] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.