Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTKB96L5)

• DOT Name: MARVEL domain-containing protein 2 (MARVELD2)
• Synonyms: Tricellulin
• Gene Name: MARVELD2
• Related Disease:
  Nonsyndromic genetic hearing loss
  Acinar cell carcinoma
  Adenocarcinoma
  Autosomal recessive nonsyndromic hearing loss 49
  Bardet biedl syndrome
  Crohn disease
  Deafness
  Nasal polyp
  Stomach cancer
  Ulcerative colitis
  leukaemia
  Leukemia
  Hearing loss, autosomal recessive
  Chronic pancreatitis
  Human papillomavirus infection
  Neoplasm
• UniProt ID: MALD2_HUMAN
• PDB ID: 5N7H; 5N7I; 5N7K
• Pfam ID: PF01284 ; PF07303
• Sequence:
  MSNDGRSRNRDRRYDEVPSDLPYQDTTIRTHPTLHDSERAVSADPLPPPPLPLQPPFGPD
  FYSSDTEEPAIAPDLKPVRRFVPDSWKNFFRGKKKDPEWDKPVSDIRYISDGVECSPPAS
  PARPNHRSPLNSCKDPYGGSEGTFSSRKEADAVFPRDPYGSLDRHTQTVRTYSEKVEEYN
  LRYSYMKSWAGLLRILGVVELLLGAGVFACVTAYIHKDSEWYNLFGYSQPYGMGGVGGLG
  SMYGGYYYTGPKTPFVLVVAGLAWITTIIILVLGMSMYYRTILLDSNWWPLTEFGINVAL
  FILYMAAAIVYVNDTNRGGLCYYPLFNTPVNAVFCRVEGGQIAAMIFLFVTMIVYLISAL
  VCLKLWRHEAARRHREYMEQQEINEPSLSSKRKMCEMATSGDRQRDSEVNFKELRTAKMK
  PELLSGHIPPGHIPKPIVMPDYVAKYPVIQTDDERERYKAVFQDQFSEYKELSAEVQAVL
  RKFDELDAVMSRLPHHSESRQEHERISRIHEEFKKKKNDPTFLEKKERCDYLKNKLSHIK
  QRIQEYDKVMNWDVQGYS
• Function: Plays a role in the formation of tricellular tight junctions and of epithelial barriers. Required for normal hearing via its role in the separation of the endolymphatic and perilymphatic spaces of the organ of Corti in the inner ear, and for normal survival of hair cells in the organ of Corti.
• KEGG Pathway: Tight junction (hsa04530)

Molecular Interaction Atlas (MIA) of This DOT

16 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Nonsyndromic genetic hearing loss	DISZX61P	Definitive	Autosomal recessive	[1]
Acinar cell carcinoma	DIS37Y0J	Strong	Altered Expression	[2]
Adenocarcinoma	DIS3IHTY	Strong	Altered Expression	[2]
Autosomal recessive nonsyndromic hearing loss 49	DISBH2UH	Strong	Autosomal recessive	[3]
Bardet biedl syndrome	DISTBNZW	Strong	Biomarker	[4]
Crohn disease	DIS2C5Q8	Strong	Biomarker	[5]
Deafness	DISKCLH4	Strong	Genetic Variation	[6]
Nasal polyp	DISLP3XE	Strong	Altered Expression	[7]
Stomach cancer	DISKIJSX	Strong	Altered Expression	[8]
Ulcerative colitis	DIS8K27O	Strong	Altered Expression	[9]
leukaemia	DISS7D1V	moderate	Altered Expression	[10]
Leukemia	DISNAKFL	moderate	Altered Expression	[10]
Hearing loss, autosomal recessive	DIS8G9R9	Supportive	Autosomal recessive	[11]
Chronic pancreatitis	DISBUOMJ	Limited	Biomarker	[12]
Human papillomavirus infection	DISX61LX	Limited	Biomarker	[13]
Neoplasm	DISZKGEW	Limited	Biomarker	[13]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of MARVEL domain-containing protein 2 (MARVELD2).	[14]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of MARVEL domain-containing protein 2 (MARVELD2).	[15]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of MARVEL domain-containing protein 2 (MARVELD2).	[16]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of MARVEL domain-containing protein 2 (MARVELD2).	[17]
Folic acid	DMEMBJC	Approved	Folic acid decreases the expression of MARVEL domain-containing protein 2 (MARVELD2).	[18]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of MARVEL domain-containing protein 2 (MARVELD2).	[20]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of MARVEL domain-containing protein 2 (MARVELD2).	[21]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of MARVEL domain-containing protein 2 (MARVELD2).	[22]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of MARVEL domain-containing protein 2 (MARVELD2).	[24]
Lithium chloride	DMHYLQ2	Investigative	Lithium chloride increases the expression of MARVEL domain-containing protein 2 (MARVELD2).	[25]

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 MARVEL domain-containing protein 2 (MARVELD2).	[19]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of MARVEL domain-containing protein 2 (MARVELD2).	[23]

References

• [1] 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.
• [2] Tricellulin expression in normal and neoplastic human pancreas.Histopathology. 2012 May;60(6B):E76-86. doi: 10.1111/j.1365-2559.2012.04189.x. Epub 2012 Mar 6.
• [3] Tricellulin is a tight-junction protein necessary for hearing. Am J Hum Genet. 2006 Dec;79(6):1040-51. doi: 10.1086/510022. Epub 2006 Oct 31.
• [4] Intrinsic protein-protein interaction-mediated and chaperonin-assisted sequential assembly of stable bardet-biedl syndrome protein complex, the BBSome.J Biol Chem. 2012 Jun 8;287(24):20625-35. doi: 10.1074/jbc.M112.341487. Epub 2012 Apr 12.
• [5] Gut Barrier Dysfunction-A Primary Defect in Twins with Crohn's Disease Predominantly Caused by Genetic Predisposition.J Crohns Colitis. 2018 Nov 9;12(10):1200-1209. doi: 10.1093/ecco-jcc/jjy045.
• [6] MARVELD2 (DFNB49) mutations in the hearing impaired Central European Roma population--prevalence, clinical impact and the common origin.PLoS One. 2015 Apr 17;10(4):e0124232. doi: 10.1371/journal.pone.0124232. eCollection 2015.
• [7] Different expressions of erbB1/2 and tight junction proteins in hypertrophic inferior turbinates and nasal polyps.Eur Arch Otorhinolaryngol. 2013 Mar;270(3):945-51. doi: 10.1007/s00405-012-2166-5. Epub 2012 Aug 28.
• [8] Negative regulation of the tight junction protein tricellulin by snail-induced epithelial-mesenchymal transition in gastric carcinoma cells.Pathobiology. 2010;77(2):106-13. doi: 10.1159/000278293. Epub 2010 Mar 22.
• [9] Tricellulin is regulated via interleukin-13-receptor 2, affects macromolecule uptake, and is decreased in ulcerative colitis.Mucosal Immunol. 2018 Mar;11(2):345-356. doi: 10.1038/mi.2017.52. Epub 2017 Jun 14.
• [10] Chemoinformatic Approach to Assess Toxicity of Ionic Liquids.Methods Mol Biol. 2018;1800:559-571. doi: 10.1007/978-1-4939-7899-1_26.
• [11] Genetic Hearing Loss Overview. 1999 Feb 14 [updated 2023 Sep 28]. 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.
• [12] Adhesion molecules and pancreatitis.J Gastroenterol. 2019 Feb;54(2):99-107. doi: 10.1007/s00535-018-1500-0. Epub 2018 Aug 23.
• [13] Altered expression of claudin-1, claudin-7, and tricellulin regardless of human papilloma virus infection in human tonsillar squamous cell carcinoma.Acta Otolaryngol. 2011 Aug;131(8):861-8. doi: 10.3109/00016489.2011.562537. Epub 2011 Apr 11.
• [14] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [15] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [16] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [17] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [18] Folic acid supplementation dysregulates gene expression in lymphoblastoid cells--implications in nutrition. Biochem Biophys Res Commun. 2011 Sep 9;412(4):688-92. doi: 10.1016/j.bbrc.2011.08.027. Epub 2011 Aug 16.
• [19] 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.
• [20] Loss of TRIM33 causes resistance to BET bromodomain inhibitors through MYC- and TGF-beta-dependent mechanisms. Proc Natl Acad Sci U S A. 2016 Aug 2;113(31):E4558-66.
• [21] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [22] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [23] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [24] Characterization of the Molecular Alterations Induced by the Prolonged Exposure of Normal Colon Mucosa and Colon Cancer Cells to Low-Dose Bisphenol A. Int J Mol Sci. 2022 Oct 1;23(19):11620. doi: 10.3390/ijms231911620.
• [25] Effects of lithium and valproic acid on gene expression and phenotypic markers in an NT2 neurosphere model of neural development. PLoS One. 2013;8(3):e58822.