Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT9Z0P1E)

• DOT Name: Catenin alpha-3 (CTNNA3)
• Synonyms: Alpha T-catenin; Cadherin-associated protein
• Gene Name: CTNNA3
• Related Disease:
  Autism
  Cytomegalovirus infection
  Intellectual disability
  Metabolic disorder
  Adult glioblastoma
  Advanced cancer
  Alzheimer disease
  Asthma
  Astrocytoma
  Carcinoma
  Cardiomyopathy
  Colorectal carcinoma
  Desmoid tumour
  Dilated cardiomyopathy 1A
  Drug dependence
  Eclampsia
  Essential tremor
  Food allergy
  Glioblastoma multiforme
  Hepatocellular carcinoma
  Hypertrophic cardiomyopathy
  Major depressive disorder
  Multiple sclerosis
  Myositis disease
  Neoplasm
  Non-alcoholic fatty liver disease
  Parkinson disease
  Substance abuse
  Substance dependence
  Transitional cell carcinoma
  Urothelial carcinoma
  Bronchopulmonary dysplasia
  Congenital heart disease
  Arrhythmia
  Arrhythmogenic right ventricular cardiomyopathy
  Arrhythmogenic right ventricular dysplasia 13
  Childhood kidney Wilms tumor
  Dilated cardiomyopathy
  Psoriatic arthritis
  Schizophrenia
  Wilms tumor
• UniProt ID: CTNA3_HUMAN
• Pfam ID: PF01044
• Sequence:
  MSAETPITLNIDPQDLQVQTFTVEKLLEPLIIQVTTLVNCPQNPSSRKKGRSKRASVLLA
  SVEEATWNLLDKGEKIAQEATVLKDELTASLEEVRKESEALKVSAERFTDDPCFLPKREA
  VVQAARALLAAVTRLLILADMIDVMCLLQHVSAFQRTFESLKNVANKSDLQKTYQKLGKE
  LENLDYLAFKRQQDLKSPNQRDEIAGARASLKENSPLLHSICSACLEHSDVASLKASKDT
  VCEEIQNALNVISNASQGIQNMTTPPEPQAATLGSALDELENLIVLNPLTVTEEEIRPSL
  EKRLEAIISGAALLADSSCTRDLHRERIIAECNAIRQALQDLLSEYMNNAGKKERSNTLN
  IALDNMCKKTRDLRRQLRKAIIDHVSDSFLDTTVPLLVLIEAAKNGREKEIKEYAAIFHE
  HTSRLVEVANLACSMSTNEDGIKIVKIAANHLETLCPQIINAALALAARPKSQAVKNTME
  MYKRTWENHIHVLTEAVDDITSIDDFLAVSESHILEDVNKCIIALRDQDADNLDRAAGAI
  RGRAARVAHIVTGEMDSYEPGAYTEGVMRNVNFLTSTVIPEFVTQVNVALEALSKSSLNV
  LDDNQFVDISKKIYDTIHDIRCSVMMIRTPEELEDVSDLEEEHEVRSHTSIQTEGKTDRA
  KMTQLPEAEKEKIAEQVADFKKVKSKLDAEIEIWDDTSNDIIVLAKNMCMIMMEMTDFTR
  GKGPLKHTTDVIYAAKMISESGSRMDVLARQIANQCPDPSCKQDLLAYLEQIKFYSHQLK
  ICSQVKAEIQNLGGELIMSALDSVTSLIQAAKNLMNAVVQTVKMSYIASTKIIRIQSPAG
  PRHPVVMWRMKAPAKKPLIKREKPEETCAAVRRGSAKKKIHPLQVMSEFRGRQIY
• Function: May be involved in formation of stretch-resistant cell-cell adhesion complexes.
• Tissue Specificity: Predominantly expressed in heart and testis. Expressed at lower levels in brain, kidney, liver and skeletal muscle.
• KEGG Pathway:
  Hippo sig.ling pathway (hsa04390)
  Adherens junction (hsa04520)
  Leukocyte transendothelial migration (hsa04670)
  Bacterial invasion of epithelial cells (hsa05100)
  Pathways in cancer (hsa05200)
  Endometrial cancer (hsa05213)
  Gastric cancer (hsa05226)
  Arrhythmogenic right ventricular cardiomyopathy (hsa05412)

Molecular Interaction Atlas (MIA) of This DOT

41 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Autism	DISV4V1Z	Definitive	Biomarker	[1]
Cytomegalovirus infection	DISCEMGC	Definitive	Genetic Variation	[2]
Intellectual disability	DISMBNXP	Definitive	Biomarker	[1]
Metabolic disorder	DIS71G5H	Definitive	Biomarker	[3]
Adult glioblastoma	DISVP4LU	Strong	Altered Expression	[4]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[5]
Alzheimer disease	DISF8S70	Strong	Genetic Variation	[6]
Asthma	DISW9QNS	Strong	Biomarker	[7]
Astrocytoma	DISL3V18	Strong	Altered Expression	[4]
Carcinoma	DISH9F1N	Strong	Genetic Variation	[8]
Cardiomyopathy	DISUPZRG	Strong	Biomarker	[9]
Colorectal carcinoma	DIS5PYL0	Strong	Genetic Variation	[10]
Desmoid tumour	DISGX357	Strong	Genetic Variation	[11]
Dilated cardiomyopathy 1A	DIS0RK9Z	Strong	Biomarker	[12]
Drug dependence	DIS9IXRC	Strong	Biomarker	[13]
Eclampsia	DISWPO8U	Strong	Genetic Variation	[14]
Essential tremor	DIS7GBKQ	Strong	Genetic Variation	[15]
Food allergy	DISMQ1BP	Strong	Genetic Variation	[16]
Glioblastoma multiforme	DISK8246	Strong	Altered Expression	[4]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[17]
Hypertrophic cardiomyopathy	DISQG2AI	Strong	Genetic Variation	[18]
Major depressive disorder	DIS4CL3X	Strong	Genetic Variation	[19]
Multiple sclerosis	DISB2WZI	Strong	Genetic Variation	[20]
Myositis disease	DISCIXF0	Strong	Biomarker	[21]
Neoplasm	DISZKGEW	Strong	Biomarker	[17]
Non-alcoholic fatty liver disease	DISDG1NL	Strong	Biomarker	[22]
Parkinson disease	DISQVHKL	Strong	Genetic Variation	[23]
Substance abuse	DIS327VW	Strong	Biomarker	[13]
Substance dependence	DISDRAAR	Strong	Biomarker	[13]
Transitional cell carcinoma	DISWVVDR	Strong	Altered Expression	[5]
Urothelial carcinoma	DISRTNTN	Strong	Altered Expression	[5]
Bronchopulmonary dysplasia	DISO0BY5	moderate	Genetic Variation	[24]
Congenital heart disease	DISQBA23	Disputed	Unknown	[25]
Arrhythmia	DISFF2NI	Limited	Altered Expression	[9]
Arrhythmogenic right ventricular cardiomyopathy	DIS3V2BE	Limited	Autosomal dominant	[25]
Arrhythmogenic right ventricular dysplasia 13	DISKZ5H3	Limited	Autosomal dominant	[26]
Childhood kidney Wilms tumor	DIS0NMK3	Limited	Genetic Variation	[27]
Dilated cardiomyopathy	DISX608J	Limited	Genetic Variation	[28]
Psoriatic arthritis	DISLWTG2	Limited	Genetic Variation	[29]
Schizophrenia	DISSRV2N	Limited	Genetic Variation	[30]
Wilms tumor	DISB6T16	Limited	Genetic Variation	[27]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
CYANATE	DM6HQDL	Investigative	Catenin alpha-3 (CTNNA3) increases the response to substance of CYANATE.	[38]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Catenin alpha-3 (CTNNA3).	[31]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Catenin alpha-3 (CTNNA3).	[32]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Catenin alpha-3 (CTNNA3).	[33]
Phenobarbital	DMXZOCG	Approved	Phenobarbital decreases the expression of Catenin alpha-3 (CTNNA3).	[34]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Catenin alpha-3 (CTNNA3).	[35]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Catenin alpha-3 (CTNNA3).	[36]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Catenin alpha-3 (CTNNA3).	[37]

References

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• [2] Infection and inflammation in schizophrenia and bipolar disorder: a genome wide study for interactions with genetic variation.PLoS One. 2015 Mar 17;10(3):e0116696. doi: 10.1371/journal.pone.0116696. eCollection 2015.
• [3] Association of CTNNB1 (beta-catenin) alterations, body mass index, and physical activity with survival in patients with colorectal cancer.JAMA. 2011 Apr 27;305(16):1685-94. doi: 10.1001/jama.2011.513.
• [4] Expression of N-cadherin and alpha-catenin in astrocytomas and glioblastomas.Br J Cancer. 1995 Sep;72(3):627-33. doi: 10.1038/bjc.1995.384.
• [5] Alpha-T-catenin (CTNNA3) displays tumour specific monoallelic expression in urothelial carcinoma of the bladder.Genes Chromosomes Cancer. 2007 Jun;46(6):587-93. doi: 10.1002/gcc.20443.
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• [11] CTNNB1 45F mutation is a molecular prognosticator of increased postoperative primary desmoid tumor recurrence: an independent, multicenter validation study.Cancer. 2013 Oct 15;119(20):3696-702. doi: 10.1002/cncr.28271. Epub 2013 Jul 31.
• [12] Intercalated disc in failing hearts from patients with dilated cardiomyopathy: Its role in the depressed left ventricular function.PLoS One. 2017 Sep 21;12(9):e0185062. doi: 10.1371/journal.pone.0185062. eCollection 2017.
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• [14] The STOX1 genotype associated with pre-eclampsia leads to a reduction of trophoblast invasion by alpha-T-catenin upregulation.Hum Mol Genet. 2010 Jul 1;19(13):2658-67. doi: 10.1093/hmg/ddq152. Epub 2010 Apr 16.
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• [16] Copy Number Variations in CTNNA3 and RBFOX1 Associate with Pediatric Food Allergy.J Immunol. 2015 Aug 15;195(4):1599-607. doi: 10.4049/jimmunol.1402310. Epub 2015 Jul 17.
• [17] CTNNA3 is a tumor suppressor in hepatocellular carcinomas and is inhibited by miR-425.Oncotarget. 2016 Feb 16;7(7):8078-89. doi: 10.18632/oncotarget.6978.
• [18] Co-inheritance of mutations associated with arrhythmogenic cardiomyopathy and hypertrophic cardiomyopathy.Eur J Hum Genet. 2017 Oct;25(10):1165-1169. doi: 10.1038/ejhg.2017.109. Epub 2017 Jul 12.
• [19] Genome-wide association study of depression phenotypes in UK Biobank identifies variants in excitatory synaptic pathways.Nat Commun. 2018 Apr 16;9(1):1470. doi: 10.1038/s41467-018-03819-3.
• [20] Risk alleles for multiple sclerosis identified by a genomewide study.N Engl J Med. 2007 Aug 30;357(9):851-62. doi: 10.1056/NEJMoa073493. Epub 2007 Jul 29.
• [21] Genetic variation in the Estonian population: pharmacogenomics study of adverse drug effects using electronic health records.Eur J Hum Genet. 2019 Mar;27(3):442-454. doi: 10.1038/s41431-018-0300-6. Epub 2018 Nov 12.
• [22] Candidate genes investigation for severe nonalcoholic fatty liver disease based on bioinformatics analysis.Medicine (Baltimore). 2017 Aug;96(32):e7743. doi: 10.1097/MD.0000000000007743.
• [23] Genome-wide genotyping in Parkinson's disease and neurologically normal controls: first stage analysis and public release of data.Lancet Neurol. 2006 Nov;5(11):911-6. doi: 10.1016/S1474-4422(06)70578-6.
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• [25] 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.
• [26] Screening of three novel candidate genes in arrhythmogenic right ventricular cardiomyopathy. Genet Test Mol Biomarkers. 2011 Apr;15(4):267-71. doi: 10.1089/gtmb.2010.0151. Epub 2011 Jan 22.
• [27] Clinical relevance of mutations in the Wilms tumor suppressor 1 gene WT1 and the cadherin-associated protein beta1 gene CTNNB1 for patients with Wilms tumors: results of long-term surveillance of 71 patients from International Society of Pediatric Oncology Study 9/Society for Pediatric Oncology.Cancer. 2008 Sep 1;113(5):1080-9. doi: 10.1002/cncr.23672.
• [28] Assessment of the CTNNA3 gene encoding human alpha T-catenin regarding its involvement in dilated cardiomyopathy.Hum Genet. 2003 Mar;112(3):227-36. doi: 10.1007/s00439-002-0857-5. Epub 2002 Dec 5.
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• [32] 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.
• [33] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [34] Dose- and time-dependent effects of phenobarbital on gene expression profiling in human hepatoma HepaRG cells. Toxicol Appl Pharmacol. 2009 Feb 1;234(3):345-60.
• [35] 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.
• [36] 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.
• [37] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [38] CTNNA3 (-catenin) gene variants are associated with diisocyanate asthma: a replication study in a Caucasian worker population. Toxicol Sci. 2013 Jan;131(1):242-6. doi: 10.1093/toxsci/kfs272. Epub 2012 Sep 13.