Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTH9H74J)

• DOT Name: Matrilin-3 (MATN3)
• Gene Name: MATN3
• Related Disease:
  Arthropathy
  Multiple epiphyseal dysplasia type 5
  Bone disease
  Chondrosarcoma
  Gastric adenocarcinoma
  Intervertebral disc degeneration
  Jeune syndrome
  Multiple epiphyseal dysplasia
  Neoplasm
  Osteoarthritis
  Osteochondrodysplasia
  Parkinson disease
  Pseudoachondroplasia
  Spondyloepimetaphyseal dysplasia
  Tuberculosis
  Type 2 collagenopathy
  Spondyloepimetaphyseal dysplasia, matrilin-3 type
• UniProt ID: MATN3_HUMAN
• Pfam ID: PF12662 ; PF07645 ; PF14670 ; PF10393 ; PF00092
• Sequence:
  MPRPAPARRLPGLLLLLWPLLLLPSAAPDPVARPGFRRLETRGPGGSPGRRPSPAAPDGA
  PASGTSEPGRARGAGVCKSRPLDLVFIIDSSRSVRPLEFTKVKTFVSRIIDTLDIGPADT
  RVAVVNYASTVKIEFQLQAYTDKQSLKQAVGRITPLSTGTMSGLAIQTAMDEAFTVEAGA
  REPSSNIPKVAIIVTDGRPQDQVNEVAARAQASGIELYAVGVDRADMASLKMMASEPLEE
  HVFYVETYGVIEKLSSRFQETFCALDPCVLGTHQCQHVCISDGEGKHHCECSQGYTLNAD
  KKTCSALDRCALNTHGCEHICVNDRSGSYHCECYEGYTLNEDRKTCSAQDKCALGTHGCQ
  HICVNDRTGSHHCECYEGYTLNADKKTCSVRDKCALGSHGCQHICVSDGAASYHCDCYPG
  YTLNEDKKTCSATEEARRLVSTEDACGCEATLAFQDKVSSYLQRLNTKLDDILEKLKINE
  YGQIHR
• Function: Major component of the extracellular matrix of cartilage and may play a role in the formation of extracellular filamentous networks.
• Tissue Specificity: Expressed only in cartilaginous tissues, such as vertebrae, ribs and shoulders.
• Reactome Pathway:
  Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs) (R-HSA-381426)
  Post-translational protein phosphorylation (R-HSA-8957275)
  ECM proteoglycans (R-HSA-3000178)

Molecular Interaction Atlas (MIA) of This DOT

17 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Arthropathy	DISVEERK	Definitive	Biomarker	[1]
Multiple epiphyseal dysplasia type 5	DIS8ZB2N	Definitive	Autosomal dominant	[2]
Bone disease	DISE1F82	Strong	Biomarker	[3]
Chondrosarcoma	DIS4I7JB	Strong	Biomarker	[4]
Gastric adenocarcinoma	DISWWLTC	Strong	Altered Expression	[5]
Intervertebral disc degeneration	DISG3AIM	Strong	Biomarker	[6]
Jeune syndrome	DISLC357	Strong	Genetic Variation	[7]
Multiple epiphyseal dysplasia	DIS5FZLR	Strong	Genetic Variation	[8]
Neoplasm	DISZKGEW	Strong	Biomarker	[9]
Osteoarthritis	DIS05URM	Strong	Biomarker	[10]
Osteochondrodysplasia	DIS9SPWW	Strong	Genetic Variation	[11]
Parkinson disease	DISQVHKL	Strong	Biomarker	[12]
Pseudoachondroplasia	DISVJW4A	Strong	Genetic Variation	[13]
Spondyloepimetaphyseal dysplasia	DISO4L5A	Strong	Genetic Variation	[14]
Tuberculosis	DIS2YIMD	Strong	Biomarker	[15]
Type 2 collagenopathy	DIS8WIDY	Strong	Genetic Variation	[16]
Spondyloepimetaphyseal dysplasia, matrilin-3 type	DISOSKAU	Supportive	Autosomal recessive	[17]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Matrilin-3 (MATN3).	[18]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Matrilin-3 (MATN3).	[21]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin affects the expression of Matrilin-3 (MATN3).	[19]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Matrilin-3 (MATN3).	[20]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Matrilin-3 (MATN3).	[22]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Matrilin-3 (MATN3).	[23]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Matrilin-3 (MATN3).	[23]
Zoledronate	DMIXC7G	Approved	Zoledronate decreases the expression of Matrilin-3 (MATN3).	[24]
Azathioprine	DMMZSXQ	Approved	Azathioprine decreases the expression of Matrilin-3 (MATN3).	[25]
Ethanol	DMDRQZU	Approved	Ethanol decreases the expression of Matrilin-3 (MATN3).	[26]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Matrilin-3 (MATN3).	[27]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of Matrilin-3 (MATN3).	[28]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Matrilin-3 (MATN3).	[29]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of Matrilin-3 (MATN3).	[30]
Coumestrol	DM40TBU	Investigative	Coumestrol decreases the expression of Matrilin-3 (MATN3).	[31]

References

• [1] Association of Matrilin-3 Gene Polymorphism with Temporomandibular Joint Internal Derangement.Genet Test Mol Biomarkers. 2016 Oct;20(10):563-568. doi: 10.1089/gtmb.2016.0037. Epub 2016 Aug 17.
• [2] Missense mutations in the beta strands of the single A-domain of matrilin-3 result in multiple epiphyseal dysplasia. J Med Genet. 2004 Jan;41(1):52-9. doi: 10.1136/jmg.2003.011429.
• [3] Structural and functional characterization of recombinant matrilin-3 A-domain and implications for human genetic bone diseases.J Biol Chem. 2007 Nov 30;282(48):34634-43. doi: 10.1074/jbc.M705301200. Epub 2007 Sep 18.
• [4] Increased expression of matrilin-3 not only in osteoarthritic articular cartilage but also in cartilage-forming tumors, and down-regulation of SOX9 via epidermal growth factor domain 1-dependent signaling.Arthritis Rheum. 2008 Sep;58(9):2798-808. doi: 10.1002/art.23761.
• [5] Martrilin-3 (MATN3) Overexpression in Gastric Adenocarcinoma and its Prognostic Significance.Med Sci Monit. 2018 Jan 18;24:348-355. doi: 10.12659/msm.908447.
• [6] Association of matrilin-3 polymorphisms with spinal disc degeneration and osteoarthritis of the first carpometacarpal joint of the hand.Ann Rheum Dis. 2006 Aug;65(8):1060-6. doi: 10.1136/ard.2005.045153. Epub 2006 Jan 5.
• [7] Alu-Alu mediated intragenic duplications in IFT81 and MATN3 are associated with skeletal dysplasias.Hum Mutat. 2018 Oct;39(10):1456-1467. doi: 10.1002/humu.23605. Epub 2018 Aug 22.
• [8] XBP1 signalling is essential for alleviating mutant protein aggregation in ER-stress related skeletal disease.PLoS Genet. 2019 Jul 1;15(7):e1008215. doi: 10.1371/journal.pgen.1008215. eCollection 2019 Jul.
• [9] pH-triggered degradable polymeric micelles for targeted anti-tumor drug delivery.Mater Sci Eng C Mater Biol Appl. 2017 Sep 1;78:912-922. doi: 10.1016/j.msec.2017.04.137. Epub 2017 Apr 25.
• [10] Downregulation of microRNA-448 inhibits IL-1-induced cartilage degradation in human chondrocytes via upregulation of matrilin-3.Cell Mol Biol Lett. 2018 Feb 22;23:7. doi: 10.1186/s11658-018-0072-6. eCollection 2018.
• [11] Multiple epiphyseal dysplasia mutations in MATN3 cause misfolding of the A-domain and prevent secretion of mutant matrilin-3.Hum Mutat. 2005 Dec;26(6):557-65. doi: 10.1002/humu.20263.
• [12] Impaired set shifting is associated with previous falls in individuals with and without Parkinson's disease.Gait Posture. 2018 May;62:220-226. doi: 10.1016/j.gaitpost.2018.02.027. Epub 2018 Mar 6.
• [13] 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.
• [14] Multiple functions of the first EGF domain in matrilin-3: Secretion and endoplasmic reticulum stress.Int J Mol Med. 2015 Dec;36(6):1648-56. doi: 10.3892/ijmm.2015.2377. Epub 2015 Oct 15.
• [15] Structure-based virtual screening, molecular dynamics simulation and MM-PBSA toward identifying the inhibitors for two-component regulatory system protein NarL of Mycobacterium Tuberculosis.J Biomol Struct Dyn. 2020 Jul;38(11):3396-3410. doi: 10.1080/07391102.2019.1657499. Epub 2019 Aug 26.
• [16] 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.
• [17] Spondylo-epi-metaphyseal dysplasia (SEMD) matrilin 3 type: homozygote matrilin 3 mutation in a novel form of SEMD. J Med Genet. 2004 May;41(5):366-72. doi: 10.1136/jmg.2003.013342.
• [18] 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.
• [19] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [20] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [21] 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.
• [22] 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.
• [23] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [24] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [25] A transcriptomics-based in vitro assay for predicting chemical genotoxicity in vivo. Carcinogenesis. 2012 Jul;33(7):1421-9.
• [26] Effects of acute ethanol treatment on NCCIT cells and NCCIT cell-derived embryoid bodies (EBs). Toxicol In Vitro. 2010 Sep;24(6):1696-704. doi: 10.1016/j.tiv.2010.05.017. Epub 2010 May 26.
• [27] 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.
• [28] Dose- and time-dependent transcriptional response of Ishikawa cells exposed to genistein. Toxicol Sci. 2016 May;151(1):71-87.
• [29] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [30] 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.
• [31] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.