Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTMPU2XQ)

• DOT Name: T-box transcription factor TBX20 (TBX20)
• Synonyms: T-box protein 20
• Gene Name: TBX20
• Related Disease:
  Atrial septal defect 4
  Dilated cardiomyopathy 1A
  Ventricular septal defect
  Arteriosclerosis
  Atherosclerosis
  Atrial septal defect
  Blepharophimosis, ptosis, and epicanthus inversus syndrome
  Cardiac disease
  Congenital heart disease
  Long QT syndrome
  Myocardial infarction
  Retinitis pigmentosa
  Squamous cell carcinoma
  Tetralogy of fallot
  Aortic aneurysm
  Cardiovascular disease
  Coronary heart disease
  Arrhythmia
  Cardiac failure
  Cardiomyopathy
  Congestive heart failure
  Dilated cardiomyopathy
• UniProt ID: TBX20_HUMAN
• Pfam ID: PF00907
• Sequence:
  MEFTASPKPQLSSRANAFSIAALMSSGGSKEKEATENTIKPLEQFVEKSSCAQPLGELTS
  LDAHGEFGGGSGSSPSSSSLCTEPLIPTTPIIPSEEMAKIACSLETKELWDKFHELGTEM
  IITKSGRRMFPTIRVSFSGVDPEAKYIVLMDIVPVDNKRYRYAYHRSSWLVAGKADPPLP
  ARLYVHPDSPFTGEQLLKQMVSFEKVKLTNNELDQHGHIILNSMHKYQPRVHIIKKKDHT
  ASLLNLKSEEFRTFIFPETVFTAVTAYQNQLITKLKIDSNPFAKGFRDSSRLTDIERESV
  ESLIQKHSYARSPIRTYGGEEDVLGDESQTTPNRGSAFTTSDNLSLSSWVSSSSSFPGFQ
  HPQSLTALGTSTASIATPIPHPIQGSLPPYSRLGMPLTPSAIASSMQGSGPTFPSFHMPR
  YHHYFQQGPYAAIQGLRHSSAVMTPFV
• Function: Acts as a transcriptional activator and repressor required for cardiac development and may have key roles in the maintenance of functional and structural phenotypes in adult heart.
• Reactome Pathway: Cardiogenesis (R-HSA-9733709)

Molecular Interaction Atlas (MIA) of This DOT

22 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Atrial septal defect 4	DISN9D8D	Definitive	Autosomal dominant	[1]
Dilated cardiomyopathy 1A	DIS0RK9Z	Definitive	Genetic Variation	[2]
Ventricular septal defect	DISICO41	Definitive	Genetic Variation	[3]
Arteriosclerosis	DISK5QGC	Strong	Biomarker	[4]
Atherosclerosis	DISMN9J3	Strong	Biomarker	[4]
Atrial septal defect	DISJT76B	Strong	Genetic Variation	[5]
Blepharophimosis, ptosis, and epicanthus inversus syndrome	DISN43YC	Strong	Biomarker	[6]
Cardiac disease	DISVO1I5	Strong	Genetic Variation	[7]
Congenital heart disease	DISQBA23	Strong	Altered Expression	[8]
Long QT syndrome	DISMKWS3	Strong	Genetic Variation	[9]
Myocardial infarction	DIS655KI	Strong	Biomarker	[10]
Retinitis pigmentosa	DISCGPY8	Strong	Biomarker	[6]
Squamous cell carcinoma	DISQVIFL	Strong	Biomarker	[11]
Tetralogy of fallot	DISMHFNW	Strong	Posttranslational Modification	[12]
Aortic aneurysm	DISQ5KRA	moderate	Biomarker	[13]
Cardiovascular disease	DIS2IQDX	moderate	Altered Expression	[13]
Coronary heart disease	DIS5OIP1	moderate	Genetic Variation	[14]
Arrhythmia	DISFF2NI	Limited	Genetic Variation	[7]
Cardiac failure	DISDC067	Limited	Biomarker	[15]
Cardiomyopathy	DISUPZRG	Limited	Genetic Variation	[16]
Congestive heart failure	DIS32MEA	Limited	Biomarker	[15]
Dilated cardiomyopathy	DISX608J	Limited	Autosomal dominant	[17]

1 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 T-box transcription factor TBX20 (TBX20).	[18]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of T-box transcription factor TBX20 (TBX20).	[19]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of T-box transcription factor TBX20 (TBX20).	[20]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of T-box transcription factor TBX20 (TBX20).	[21]

References

• [1] A gain-of-function TBX20 mutation causes congenital atrial septal defects, patent foramen ovale and cardiac valve defects. J Med Genet. 2010 Apr;47(4):230-5. doi: 10.1136/jmg.2009.069997. Epub 2009 Sep 16.
• [2] Identification and Functional Characterization of an ISL1 Mutation Predisposing to Dilated Cardiomyopathy.J Cardiovasc Transl Res. 2019 Jun;12(3):257-267. doi: 10.1007/s12265-018-9851-8. Epub 2018 Dec 10.
• [3] Novel mutations in the transcriptional activator domain of the human TBX20 in patients with atrial septal defect.Biomed Res Int. 2015;2015:718786. doi: 10.1155/2015/718786. Epub 2015 Mar 5.
• [4] T-box20 suppresses oxidized low-density lipoprotein-induced human vascular endothelial cell injury by upregulation of PPAR-.Cell Physiol Biochem. 2013;32(5):1137-50. doi: 10.1159/000354514. Epub 2013 Nov 11.
• [5] A novel TBX20 lossoffunction mutation contributes to adultonset dilated cardiomyopathy or congenital atrial septal defect.Mol Med Rep. 2016 Oct;14(4):3307-14. doi: 10.3892/mmr.2016.5609. Epub 2016 Aug 9.
• [6] Characterization of the human TBX20 gene, a new member of the T-Box gene family closely related to the Drosophila H15 gene.Genomics. 2000 Aug 1;67(3):317-32. doi: 10.1006/geno.2000.6249.
• [7] Tbx20 regulates a genetic program essential to adult mouse cardiomyocyte function.J Clin Invest. 2011 Dec;121(12):4640-54. doi: 10.1172/JCI59472. Epub 2011 Nov 14.
• [8] TBX20 Regulates Angiogenesis Through the Prokineticin 2-Prokineticin Receptor 1 Pathway.Circulation. 2018 Aug 28;138(9):913-928. doi: 10.1161/CIRCULATIONAHA.118.033939.
• [9] Tbx20 controls the expression of the KCNH2 gene and of hERG channels.Proc Natl Acad Sci U S A. 2017 Jan 17;114(3):E416-E425. doi: 10.1073/pnas.1612383114. Epub 2017 Jan 3.
• [10] Cardiogenic genes expressed in cardiac fibroblasts contribute to heart development and repair.Circ Res. 2014 Apr 25;114(9):1422-34. doi: 10.1161/CIRCRESAHA.114.302530. Epub 2014 Mar 20.
• [11] Genome-wide methylome analysis using MethylCap-seq uncovers 4 hypermethylated markers with high sensitivity for both adeno- and squamous-cell cervical carcinoma.Oncotarget. 2016 Dec 6;7(49):80735-80750. doi: 10.18632/oncotarget.12598.
• [12] DNA methylation status of TBX20 in patients with tetralogy of Fallot.BMC Med Genomics. 2019 May 28;12(1):75. doi: 10.1186/s12920-019-0534-3.
• [13] Copy number variation analysis in bicuspid aortic valve-related aortopathy identifies TBX20 as a contributing gene.Eur J Hum Genet. 2019 Jul;27(7):1033-1043. doi: 10.1038/s41431-019-0364-y. Epub 2019 Feb 28.
• [14] Identification of 64 Novel Genetic Loci Provides an Expanded View on the Genetic Architecture of Coronary Artery Disease.Circ Res. 2018 Feb 2;122(3):433-443. doi: 10.1161/CIRCRESAHA.117.312086. Epub 2017 Dec 6.
• [15] A context-specific cardiac -catenin and GATA4 interaction influences TCF7L2 occupancy and remodels chromatin driving disease progression in the adult heart.Nucleic Acids Res. 2018 Apr 6;46(6):2850-2867. doi: 10.1093/nar/gky049.
• [16] Mutations in cardiac T-box factor gene TBX20 are associated with diverse cardiac pathologies, including defects of septation and valvulogenesis and cardiomyopathy.Am J Hum Genet. 2007 Aug;81(2):280-91. doi: 10.1086/519530. Epub 2007 Jun 15.
• [17] 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.
• [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] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [20] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [21] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.