Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT53H5U6)

• DOT Name: Cartilage-associated protein (CRTAP)
• Gene Name: CRTAP
• Related Disease:
  Advanced cancer
  Gastric cancer
  Multiple sclerosis
  Non-small-cell lung cancer
  Stomach cancer
  Bone disease
  Brain neoplasm
  Cole-Carpenter syndrome
  Colorectal carcinoma
  Connective tissue disorder
  Dementia
  Depression
  Head-neck squamous cell carcinoma
  Hepatocellular carcinoma
  Lung cancer
  Lung carcinoma
  Major depressive disorder
  Morquio syndrome
  Osteogenesis imperfecta
  Osteogenesis imperfecta type 1
  Osteogenesis imperfecta type 7
  Periodontal disease
  Plasma cell myeloma
  X-linked scapuloperoneal muscular dystrophy
  Gastrointestinal stromal tumour
  Non-hodgkin lymphoma
  Osteogenesis imperfecta type 2
  Osteogenesis imperfecta type 3
  Osteogenesis imperfecta type 4
  Osteoporosis
• UniProt ID: CRTAP_HUMAN
• Sequence:
  MEPGRRGAAALLALLCVACALRAGRAQYERYSFRSFPRDELMPLESAYRHALDKYSGEHW
  AESVGYLEISLRLHRLLRDSEAFCHRNCSAAPQPEPAAGLASYPELRLFGGLLRRAHCLK
  RCKQGLPAFRQSQPSREVLADFQRREPYKFLQFAYFKANNLPKAIAAAHTFLLKHPDDEM
  MKRNMAYYKSLPGAEDYIKDLETKSYESLFIRAVRAYNGENWRTSITDMELALPDFFKAF
  YECLAACEGSREIKDFKDFYLSIADHYVEVLECKIQCEENLTPVIGGYPVEKFVATMYHY
  LQFAYYKLNDLKNAAPCAVSYLLFDQNDKVMQQNLVYYQYHRDTWGLSDEHFQPRPEAVQ
  FFNVTTLQKELYDFAKENIMDDDEGEVVEYVDDLLELEETS
• Function: Necessary for efficient 3-hydroxylation of fibrillar collagen prolyl residues.
• Tissue Specificity: Found in articular chondrocytes. Expressed in a variety of tissues.
• Reactome Pathway: Collagen biosynthesis and modifying enzymes (R-HSA-1650814)

Molecular Interaction Atlas (MIA) of This DOT

30 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Definitive	Biomarker	[1]
Gastric cancer	DISXGOUK	Definitive	Biomarker	[2]
Multiple sclerosis	DISB2WZI	Definitive	Biomarker	[3]
Non-small-cell lung cancer	DIS5Y6R9	Definitive	Genetic Variation	[4]
Stomach cancer	DISKIJSX	Definitive	Biomarker	[2]
Bone disease	DISE1F82	Strong	Genetic Variation	[5]
Brain neoplasm	DISY3EKS	Strong	Altered Expression	[6]
Cole-Carpenter syndrome	DISTWF6O	Strong	Genetic Variation	[7]
Colorectal carcinoma	DIS5PYL0	Strong	Genetic Variation	[8]
Connective tissue disorder	DISKXBS3	Strong	Biomarker	[9]
Dementia	DISXL1WY	Strong	Biomarker	[10]
Depression	DIS3XJ69	Strong	Biomarker	[10]
Head-neck squamous cell carcinoma	DISF7P24	Strong	Genetic Variation	[11]
Hepatocellular carcinoma	DIS0J828	Strong	Genetic Variation	[12]
Lung cancer	DISCM4YA	Strong	Genetic Variation	[13]
Lung carcinoma	DISTR26C	Strong	Genetic Variation	[13]
Major depressive disorder	DIS4CL3X	Strong	Genetic Variation	[14]
Morquio syndrome	DIS2Y2P2	Strong	Genetic Variation	[15]
Osteogenesis imperfecta	DIS7XQSD	Strong	Genetic Variation	[16]
Osteogenesis imperfecta type 1	DISPEDS3	Strong	Biomarker	[17]
Osteogenesis imperfecta type 7	DIS51PPY	Strong	Autosomal recessive	[18]
Periodontal disease	DISJQHVN	Strong	Genetic Variation	[19]
Plasma cell myeloma	DIS0DFZ0	Strong	Genetic Variation	[20]
X-linked scapuloperoneal muscular dystrophy	DISBYRCR	Strong	Genetic Variation	[11]
Gastrointestinal stromal tumour	DIS6TJYS	moderate	Genetic Variation	[21]
Non-hodgkin lymphoma	DISS2Y8A	moderate	Genetic Variation	[22]
Osteogenesis imperfecta type 2	DISMGSS3	Supportive	Autosomal dominant	[23]
Osteogenesis imperfecta type 3	DISFJVSJ	Supportive	Autosomal dominant	[23]
Osteogenesis imperfecta type 4	DIS8S46L	Supportive	Autosomal dominant	[23]
Osteoporosis	DISF2JE0	Limited	Genetic Variation	[24]

3 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 Cartilage-associated protein (CRTAP).	[25]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Cartilage-associated protein (CRTAP).	[31]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Cartilage-associated protein (CRTAP).	[37]

13 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 Cartilage-associated protein (CRTAP).	[26]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Cartilage-associated protein (CRTAP).	[27]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Cartilage-associated protein (CRTAP).	[28]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Cartilage-associated protein (CRTAP).	[29]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Cartilage-associated protein (CRTAP).	[30]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Cartilage-associated protein (CRTAP).	[32]
Marinol	DM70IK5	Approved	Marinol increases the expression of Cartilage-associated protein (CRTAP).	[33]
Demecolcine	DMCZQGK	Approved	Demecolcine decreases the expression of Cartilage-associated protein (CRTAP).	[34]
Cytarabine	DMZD5QR	Approved	Cytarabine decreases the expression of Cartilage-associated protein (CRTAP).	[35]
Benzatropine	DMF7EXL	Approved	Benzatropine increases the expression of Cartilage-associated protein (CRTAP).	[36]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Cartilage-associated protein (CRTAP).	[38]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Cartilage-associated protein (CRTAP).	[39]
Glyphosate	DM0AFY7	Investigative	Glyphosate increases the expression of Cartilage-associated protein (CRTAP).	[40]

References

• [1] Polymorphisms in the Caspase7 gene and the risk of lung cancer.Lung Cancer. 2009 Jul;65(1):19-24. doi: 10.1016/j.lungcan.2008.10.022. Epub 2008 Dec 6.
• [2] Prognostic significance of mRNA expression of CASPs in gastric cancer.Oncol Lett. 2019 Nov;18(5):4535-4554. doi: 10.3892/ol.2019.10816. Epub 2019 Sep 5.
• [3] CASP-9: A susceptibility locus for multiple sclerosis in Italy.J Neuroimmunol. 2009 May 29;210(1-2):100-3. doi: 10.1016/j.jneuroim.2009.03.013. Epub 2009 Apr 8.
• [4] Polymorphisms in the CASPASE genes and survival in patients with early-stage non-small-cell lung cancer.J Clin Oncol. 2009 Dec 1;27(34):5823-9. doi: 10.1200/JCO.2009.23.1738. Epub 2009 Oct 13.
• [5] Prolyl 3-hydroxylase 1 deficiency causes a recessive metabolic bone disorder resembling lethal/severe osteogenesis imperfecta. Nat Genet. 2007 Mar;39(3):359-65. doi: 10.1038/ng1968. Epub 2007 Feb 4.
• [6] HER2 Heterogeneity Is Associated with Poor Survival in HER2-Positive Breast Cancer.Int J Mol Sci. 2018 Jul 24;19(8):2158. doi: 10.3390/ijms19082158.
• [7] CRTAP mutation in a patient with Cole-Carpenter syndrome.Am J Med Genet A. 2015 Mar;167A(3):587-91. doi: 10.1002/ajmg.a.36916. Epub 2015 Jan 21.
• [8] Association of CASP9, CASP10 gene polymorphisms and tea drinking with colorectal cancer risk in the Han Chinese population.J Zhejiang Univ Sci B. 2013 Jan;14(1):47-57. doi: 10.1631/jzus.B1200218.
• [9] CRTAP is required for prolyl 3- hydroxylation and mutations cause recessive osteogenesis imperfecta. Cell. 2006 Oct 20;127(2):291-304. doi: 10.1016/j.cell.2006.08.039.
• [10] The psychometric properties of the control, autonomy, self-realisation and pleasure scale (CASP-19) for older adults with dementia.Aging Ment Health. 2019 May;23(5):643-649. doi: 10.1080/13607863.2018.1428940. Epub 2018 Jan 22.
• [11] A functional variant at the miR-885-5p binding site of CASP3 confers risk of both index and second primary malignancies in patients with head and neck cancer.FASEB J. 2013 Apr;27(4):1404-12. doi: 10.1096/fj.12-223420. Epub 2012 Dec 27.
• [12] Caspase polymorphisms and prognosis of hepatocellular carcinoma.PLoS One. 2017 Apr 28;12(4):e0176802. doi: 10.1371/journal.pone.0176802. eCollection 2017.
• [13] A literature-based systematic HuGE review and meta-analysis show that CASP gene family polymorphisms are associated with risk of lung cancer.Genet Mol Res. 2013 Jan 4;12(3):3057-69. doi: 10.4238/2013.January.4.22.
• [14] Genome-wide meta-analyses of stratified depression in Generation Scotland and UK Biobank.Transl Psychiatry. 2018 Jan 10;8(1):9. doi: 10.1038/s41398-017-0034-1.
• [15] Null mutations in LEPRE1 and CRTAP cause severe recessive osteogenesis imperfecta.Cell Tissue Res. 2010 Jan;339(1):59-70. doi: 10.1007/s00441-009-0872-0. Epub 2009 Oct 28.
• [16] Identification of a Candidate Mutation in the COL1A2 Gene of a Chow Chow With Osteogenesis Imperfecta.J Hered. 2018 Mar 16;109(3):308-314. doi: 10.1093/jhered/esx074.
• [17] CRTAP and LEPRE1 mutations in recessive osteogenesis imperfecta.Hum Mutat. 2008 Dec;29(12):1435-42. doi: 10.1002/humu.20799.
• [18] 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.
• [19] Assessment of CASP gene polymorphisms in periodontal disease.Genet Mol Res. 2015 Dec 22;14(4):18069-77. doi: 10.4238/2015.December.22.33.
• [20] Caspase polymorphisms and genetic susceptibility to multiple myeloma.Hematol Oncol. 2008 Sep;26(3):148-51. doi: 10.1002/hon.852.
• [21] Mutational analysis of CASP1, 2, 3, 4, 5, 6, 7, 8, 9, 10, and 14 genes in gastrointestinal stromal tumors.Hum Pathol. 2009 Jun;40(6):868-71. doi: 10.1016/j.humpath.2008.11.013. Epub 2009 Mar 9.
• [22] Genetic variants in caspase genes and susceptibility to non-Hodgkin lymphoma.Carcinogenesis. 2007 Apr;28(4):823-7. doi: 10.1093/carcin/bgl196. Epub 2006 Oct 27.
• [23] Nosology and classification of genetic skeletal disorders: 2010 revision. Am J Med Genet A. 2011 May;155A(5):943-68. doi: 10.1002/ajmg.a.33909. Epub 2011 Mar 15.
• [24] Common variants in FLNB/CRTAP, not ARHGEF3 at 3p, are associated with osteoporosis in southern Chinese women.Osteoporos Int. 2010 Jun;21(6):1009-20. doi: 10.1007/s00198-009-1043-6. Epub 2009 Sep 1.
• [25] 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.
• [26] 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.
• [27] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [28] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [29] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [30] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [31] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [32] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [33] Delta9-tetrahydrocannabinol inhibits cytotrophoblast cell proliferation and modulates gene transcription. Mol Hum Reprod. 2006 May;12(5):321-33. doi: 10.1093/molehr/gal036. Epub 2006 Apr 5.
• [34] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [35] Cytosine arabinoside induces ectoderm and inhibits mesoderm expression in human embryonic stem cells during multilineage differentiation. Br J Pharmacol. 2011 Apr;162(8):1743-56.
• [36] Cannabidiol Displays Proteomic Similarities to Antipsychotics in Cuprizone-Exposed Human Oligodendrocytic Cell Line MO3.13. Front Mol Neurosci. 2021 May 28;14:673144. doi: 10.3389/fnmol.2021.673144. eCollection 2021.
• [37] 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.
• [38] Alternatives for the worse: Molecular insights into adverse effects of bisphenol a and substitutes during human adipocyte differentiation. Environ Int. 2021 Nov;156:106730. doi: 10.1016/j.envint.2021.106730. Epub 2021 Jun 27.
• [39] 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.
• [40] Evaluation of estrogen receptor alpha activation by glyphosate-based herbicide constituents. Food Chem Toxicol. 2017 Oct;108(Pt A):30-42.