Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTULXVE0)

• DOT Name: Contactin-4 (CNTN4)
• Synonyms: Brain-derived immunoglobulin superfamily protein 2; BIG-2
• Gene Name: CNTN4
• Related Disease:
  Cerebellar degeneration
  Oral cancer
  Alcohol dependence
  Anorexia nervosa cachexia
  Benign neoplasm
  Bipolar disorder
  Breast cancer
  Breast carcinoma
  Chronic obstructive pulmonary disease
  Intellectual disability
  Mental disorder
  Neurodevelopmental disorder
  Obesity
  Paraganglioma
  Pervasive developmental disorder
  Pheochromocytoma
  Schizophrenia
  Trichohepatoenteric syndrome
  Autism
  Epithelial ovarian cancer
  Gallbladder cancer
  High blood pressure
  Neoplasm
  Ovarian cancer
  Ovarian neoplasm
  Autism spectrum disorder
  OPTN-related open angle glaucoma
  Complex neurodevelopmental disorder
• UniProt ID: CNTN4_HUMAN
• Pfam ID: PF00041 ; PF07679 ; PF13927
• Sequence:
  MRLPWELLVLQSFILCLADDSTLHGPIFIQEPSPVMFPLDSEEKKVKLNCEVKGNPKPHI
  RWKLNGTDVDTGMDFRYSVVEGSLLINNPNKTQDAGTYQCTATNSFGTIVSREAKLQFAY
  LDNFKTRTRSTVSVRRGQGMVLLCGPPPHSGELSYAWIFNEYPSYQDNRRFVSQETGNLY
  IAKVEKSDVGNYTCVVTNTVTNHKVLGPPTPLILRNDGVMGEYEPKIEVQFPETVPTAKG
  ATVKLECFALGNPVPTIIWRRADGKPIARKARRHKSNGILEIPNFQQEDAGLYECVAENS
  RGKNVARGQLTFYAQPNWIQKINDIHVAMEENVFWECKANGRPKPTYKWLKNGEPLLTRD
  RIQIEQGTLNITIVNLSDAGMYQCLAENKHGVIFSNAELSVIAVGPDFSRTLLKRVTLVK
  VGGEVVIECKPKASPKPVYTWKKGRDILKENERITISEDGNLRIINVTKSDAGSYTCIAT
  NHFGTASSTGNLVVKDPTRVMVPPSSMDVTVGESIVLPCQVTHDHSLDIVFTWSFNGHLI
  DFDRDGDHFERVGGQDSAGDLMIRNIQLKHAGKYVCMVQTSVDRLSAAADLIVRGPPGPP
  EAVTIDEITDTTAQLSWRPGPDNHSPITMYVIQARTPFSVGWQAVSTVPELIDGKTFTAT
  VVGLNPWVEYEFRTVAANVIGIGEPSRPSEKRRTEEALPEVTPANVSGGGGSKSELVITW
  ETVPEELQNGRGFGYVVAFRPYGKMIWMLTVLASADASRYVFRNESVHPFSPFEVKVGVF
  NNKGEGPFSPTTVVYSAEEEPTKPPASIFARSLSATDIEVFWASPLEKNRGRIQGYEVKY
  WRHEDKEENARKIRTVGNQTSTKITNLKGSVLYHLAVKAYNSAGTGPSSATVNVTTRKPP
  PSQPPGNIIWNSSDSKIILNWDQVKALDNESEVKGYKVLYRWNRQSSTSVIETNKTSVEL
  SLPFDEDYIIEIKPFSDGGDGSSSEQIRIPKISNAYARGSGASTSNACTLSAISTIMISL
  TARSSL
• Function: Contactins mediate cell surface interactions during nervous system development. Has some neurite outgrowth-promoting activity. May be involved in synaptogenesis.
• Tissue Specificity: Mainly expressed in brain. Highly expressed in cerebellum and weakly expressed in corpus callosum, caudate nucleus, amygdala and spinal cord. Also expressed in testis, pancreas, thyroid, uterus, small intestine and kidney. Not expressed in skeletal muscle. Isoform 2 is weakly expressed in cerebral cortex.
• Reactome Pathway: Post-translational modification (R-HSA-163125)

Molecular Interaction Atlas (MIA) of This DOT

28 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Cerebellar degeneration	DISPBCM3	Definitive	Biomarker	[1]
Oral cancer	DISLD42D	Definitive	Genetic Variation	[2]
Alcohol dependence	DIS4ZSCO	Strong	Biomarker	[3]
Anorexia nervosa cachexia	DISFO5RQ	Strong	Biomarker	[4]
Benign neoplasm	DISDUXAD	Strong	Altered Expression	[5]
Bipolar disorder	DISAM7J2	Strong	Biomarker	[3]
Breast cancer	DIS7DPX1	Strong	Biomarker	[6]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[6]
Chronic obstructive pulmonary disease	DISQCIRF	Strong	Genetic Variation	[7]
Intellectual disability	DISMBNXP	Strong	Biomarker	[4]
Mental disorder	DIS3J5R8	Strong	Genetic Variation	[8]
Neurodevelopmental disorder	DIS372XH	Strong	Biomarker	[4]
Obesity	DIS47Y1K	Strong	Biomarker	[9]
Paraganglioma	DIS2XXH5	Strong	Altered Expression	[5]
Pervasive developmental disorder	DIS51975	Strong	Biomarker	[10]
Pheochromocytoma	DIS56IFV	Strong	Altered Expression	[5]
Schizophrenia	DISSRV2N	Strong	Genetic Variation	[11]
Trichohepatoenteric syndrome	DISL3ODF	Strong	Biomarker	[12]
Autism	DISV4V1Z	moderate	Biomarker	[13]
Epithelial ovarian cancer	DIS56MH2	moderate	Altered Expression	[14]
Gallbladder cancer	DISXJUAF	moderate	Genetic Variation	[15]
High blood pressure	DISY2OHH	moderate	Altered Expression	[16]
Neoplasm	DISZKGEW	moderate	Biomarker	[14]
Ovarian cancer	DISZJHAP	moderate	Biomarker	[14]
Ovarian neoplasm	DISEAFTY	moderate	Biomarker	[14]
Autism spectrum disorder	DISXK8NV	Disputed	Autosomal dominant	[17]
OPTN-related open angle glaucoma	DISDR98A	Disputed	Biomarker	[18]
Complex neurodevelopmental disorder	DISB9AFI	Limited	Autosomal dominant	[19]

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 Contactin-4 (CNTN4).	[20]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Contactin-4 (CNTN4).	[25]

5 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 Contactin-4 (CNTN4).	[21]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Contactin-4 (CNTN4).	[22]
Malathion	DMXZ84M	Approved	Malathion increases the expression of Contactin-4 (CNTN4).	[23]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Contactin-4 (CNTN4).	[24]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A decreases the expression of Contactin-4 (CNTN4).	[24]

References

• [1] The contactin 4 gene locus at 3p26 is a candidate gene of SCA16.Neurology. 2006 Oct 10;67(7):1236-41. doi: 10.1212/01.wnl.0000238510.84932.82.
• [2] Single nucleotide polymorphisms in an Indian cohort and association of CNTN4, MMP2 and SNTB1 variants with oral cancer.Cancer Genet. 2017 Aug;214-215:16-25. doi: 10.1016/j.cancergen.2017.03.006. Epub 2017 Mar 23.
• [3] Genome-wide association study in bipolar patients stratified by co-morbidity.PLoS One. 2011;6(12):e28477. doi: 10.1371/journal.pone.0028477. Epub 2011 Dec 21.
• [4] A current view on contactin-4, -5, and -6: Implications in neurodevelopmental disorders.Mol Cell Neurosci. 2017 Jun;81:72-83. doi: 10.1016/j.mcn.2016.12.004. Epub 2017 Jan 5.
• [5] Expression of Contactin 4 Is Associated With Malignant Behavior in Pheochromocytomas and Paragangliomas.J Clin Endocrinol Metab. 2018 Jan 1;103(1):46-55. doi: 10.1210/jc.2017-01314.
• [6] Pregnancies during and after trastuzumab and/or lapatinib in patients with human epidermal growth factor receptor 2-positive early breast cancer: Analysis from the NeoALTTO (BIG 1-06) and ALTTO (BIG 2-06) trials.Cancer. 2019 Jan 15;125(2):307-316. doi: 10.1002/cncr.31784. Epub 2018 Oct 18.
• [7] Body mass index change in gastrointestinal cancer and chronic obstructive pulmonary disease is associated with Dedicator of Cytokinesis 1.J Cachexia Sarcopenia Muscle. 2017 Jun;8(3):428-436. doi: 10.1002/jcsm.12171. Epub 2017 Jan 2.
• [8] Nanomechanics of multidomain neuronal cell adhesion protein contactin revealed by single molecule AFM and SMD.Sci Rep. 2017 Aug 18;7(1):8852. doi: 10.1038/s41598-017-09482-w.
• [9] Obesity-insulin targeted genes in the 3p26-25 region in human studies and LG/J and SM/J mice.Metabolism. 2012 Aug;61(8):1129-41. doi: 10.1016/j.metabol.2012.01.008. Epub 2012 Mar 3.
• [10] Disruption of contactin 4 in three subjects with autism spectrum disorder.J Med Genet. 2009 Mar;46(3):176-82. doi: 10.1136/jmg.2008.057505. Epub 2008 Mar 18.
• [11] Genome-Wide Association Study Detected Novel Susceptibility Genes for Schizophrenia and Shared Trans-Populations/Diseases Genetic Effect.Schizophr Bull. 2019 Jun 18;45(4):824-834. doi: 10.1093/schbul/sby140.
• [12] Microarray based analysis of an inherited terminal 3p26.3 deletion, containing only the CHL1 gene, from a normal father to his two affected children.Orphanet J Rare Dis. 2011 Apr 1;6:12. doi: 10.1186/1750-1172-6-12.
• [13] Contactins in the neurobiology of autism.Eur J Pharmacol. 2013 Nov 5;719(1-3):63-74. doi: 10.1016/j.ejphar.2013.07.016. Epub 2013 Jul 17.
• [14] Molecular genetic analysis of a cell adhesion molecule with homology to L1CAM, contactin 6, and contactin 4 candidate chromosome 3p26pter tumor suppressor genes in ovarian cancer.Int J Gynecol Cancer. 2009 May;19(4):513-25. doi: 10.1111/IGC.0b013e3181a3cd38.
• [15] A genome-wide association study identifies SNP in DCC is associated with gallbladder cancer in the Japanese population.J Hum Genet. 2012 Apr;57(4):235-7. doi: 10.1038/jhg.2012.9. Epub 2012 Feb 9.
• [16] Genetic mapping of habitual substance use, obesity-related traits, responses to mental and physical stress, and heart rate and blood pressure measurements reveals shared genes that are overrepresented in the neural synapse.Hypertens Res. 2012 Jun;35(6):585-91. doi: 10.1038/hr.2011.233. Epub 2012 Feb 2.
• [17] Disruption of contactin 4 (CNTN4) results in developmental delay and other features of 3p deletion syndrome. Am J Hum Genet. 2004 Jun;74(6):1286-93. doi: 10.1086/421474. Epub 2004 Apr 21.
• [18] Gene-rich large deletions are overrepresented in POAG patients of Indian and Caucasian origins.Invest Ophthalmol Vis Sci. 2014 Apr 24;55(5):3258-64. doi: 10.1167/iovs.14-14339.
• [19] 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.
• [20] 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.
• [21] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [22] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [23] Exposure to Insecticides Modifies Gene Expression and DNA Methylation in Hematopoietic Tissues In Vitro. Int J Mol Sci. 2023 Mar 26;24(7):6259. doi: 10.3390/ijms24076259.
• [24] Inhibition of CXCL12-mediated chemotaxis of Jurkat cells by direct immunotoxicants. Arch Toxicol. 2016 Jul;90(7):1685-94. doi: 10.1007/s00204-015-1585-7. Epub 2015 Aug 28.
• [25] 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.