Details of Drug Off-Target (DOT)

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

• DOT Name: Contactin-6 (CNTN6)
• Synonyms: Neural recognition molecule NB-3; hNB-3
• Gene Name: CNTN6
• Related Disease:
  Cone-rod dystrophy 2
  Schizophrenia
  Alcohol dependence
  Autism
  Autism spectrum disorder
  Autosomal recessive juvenile Parkinson disease 2
  Bipolar disorder
  Differentiated thyroid carcinoma
  Epilepsy
  Intellectual disability
  Neurodevelopmental disorder
  Systemic lupus erythematosus
  Anorexia nervosa cachexia
  Attention deficit hyperactivity disorder
  Epithelial ovarian cancer
  Complex neurodevelopmental disorder
  Tourette syndrome
• UniProt ID: CNTN6_HUMAN
• Pfam ID: PF00041 ; PF07679 ; PF13927
• Sequence:
  MRLLWKLVILLPLINSSAGDGLLSRPIFTQEPHDVIFPLDLSKSEVILNCAANGYPSPHY
  RWKQNGTDIDFTMSYHYRLDGGSLAINSPHTDQDIGMYQCLATNLLGTILSRKAKLQFAY
  IEDFETKTRSTVSVREGQGVVLLCGPPPHFGDLSYAWTFNDNPLYVQEDNRRFVSQETGN
  LYIAKVEPSDVGNYTCFITNKEAQRSVQGPPTPLVQRTDGVMGEYEPKIEVRFPETIQAA
  KDSSVKLECFALGNPVPDISWRRLDGSPLPGKVKYSKSQAILEIPNFQQEDEGFYECIAS
  NLRGRNLAKGQLIFYAPPEWEQKIQNTHLSIYDNLLWECKASGKPNPWYTWLKNGERLNP
  EERIQIENGTLIITMLNVSDSGVYQCAAENKYQIIYANAELRVLASAPDFSKSPVKKKSF
  VQVGGDIVIGCKPNAFPRAAISWKRGTETLRQSKRIFLLEDGSLKIYNITRSDAGSYTCI
  ATNQFGTAKNTGSLIVKERTVITVPPSKMDVTVGESIVLPCQVSHDPSIEVVFVWFFNGD
  VIDLKKGVAHFERIGGESVGDLMIRNIQLHHSGKYLCTVQTTLESLSAVADIIVRGPPGP
  PEDVQVEDISSTTSQLSWRAGPDNNSPIQIFTIQTRTPFSVGWQAVATVPEILNGKTYNA
  TVVGLSPWVEYEFRVVAGNSIGIGEPSEPSELLRTKASVPVVAPVNIHGGGGSRSELVIT
  WESIPEELQNGEGFGYIIMFRPVGSTTWSKEKVSSVESSRFVYRNESIIPLSPFEVKVGV
  YNNEGEGSLSTVTIVYSGEDEPQLAPRGTSLQSFSASEMEVSWNAIAWNRNTGRVLGYEV
  LYWTDDSKESMIGKIRVSGNVTTKNITGLKANTIYFASVRAYNTAGTGPSSPPVNVTTKK
  SPPSQPPANIAWKLTNSKLCLNWEHVKTMENESEVLGYKILYRQNRQSKTHILETNNTSA
  ELLVPFEEDYLIEIRTVSDGGDGSSSEEIRIPKMSSLSSRGIQFLEPSTHFLSIVIVIFH
  CFAIQPLI
• Function: Contactins mediate cell surface interactions during nervous system development. Participates in oligodendrocytes generation by acting as a ligand of NOTCH1. Its association with NOTCH1 promotes NOTCH1 activation through the released notch intracellular domain (NICD) and subsequent translocation to the nucleus. Involved in motor coordination.
• Tissue Specificity: Expressed in nervous system. Highly expressed in cerebellum. Expressed at intermediate level in thalamus, subthalamic nucleus. Weakly expressed in corpus callosum, caudate nucleus and spinal cord.
• Reactome Pathway: CHL1 interactions (R-HSA-447041)

Molecular Interaction Atlas (MIA) of This DOT

17 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Cone-rod dystrophy 2	DISX2RWY	Definitive	Biomarker	[1]
Schizophrenia	DISSRV2N	Definitive	Genetic Variation	[2]
Alcohol dependence	DIS4ZSCO	Strong	Biomarker	[3]
Autism	DISV4V1Z	Strong	Altered Expression	[4]
Autism spectrum disorder	DISXK8NV	Strong	Biomarker	[5]
Autosomal recessive juvenile Parkinson disease 2	DISNSTD1	Strong	Biomarker	[6]
Bipolar disorder	DISAM7J2	Strong	Biomarker	[7]
Differentiated thyroid carcinoma	DIS1V20Y	Strong	Biomarker	[8]
Epilepsy	DISBB28L	Strong	Genetic Variation	[2]
Intellectual disability	DISMBNXP	Strong	Genetic Variation	[9]
Neurodevelopmental disorder	DIS372XH	Strong	Biomarker	[5]
Systemic lupus erythematosus	DISI1SZ7	Strong	Genetic Variation	[10]
Anorexia nervosa cachexia	DISFO5RQ	moderate	Biomarker	[7]
Attention deficit hyperactivity disorder	DISL8MX9	moderate	Biomarker	[7]
Epithelial ovarian cancer	DIS56MH2	moderate	Altered Expression	[11]
Complex neurodevelopmental disorder	DISB9AFI	Disputed	Autosomal dominant	[12]
Tourette syndrome	DISX9D54	Limited	Unknown	[13]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Contactin-6 (CNTN6).	[14]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Contactin-6 (CNTN6).	[15]
Folic acid	DMEMBJC	Approved	Folic acid decreases the expression of Contactin-6 (CNTN6).	[16]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Contactin-6 (CNTN6).	[18]

1 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 Contactin-6 (CNTN6).	[17]

References

• [1] Induced NB-3 Limits Regenerative Potential of Serotonergic Axons after Complete Spinal Transection.J Neurotrauma. 2019 Feb 1;36(3):436-447. doi: 10.1089/neu.2018.5652. Epub 2018 Oct 10.
• [2] Schizophrenia and epilepsy as a result of maternally inherited CNTN6 copy number variant.Schizophr Res. 2018 Dec;202:111-112. doi: 10.1016/j.schres.2018.06.062. Epub 2018 Jul 6.
• [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] Decreased Expression of Synaptophysin 1 (SYP1 Major Synaptic Vesicle Protein p38) and Contactin 6 (CNTN6/NB3) in the Cerebellar Vermis of reln Haplodeficient Mice.Cell Mol Neurobiol. 2019 Aug;39(6):833-856. doi: 10.1007/s10571-019-00683-7. Epub 2019 May 16.
• [5] CNTN6 copy number variations: Uncertain clinical significance in individuals with neurodevelopmental disorders.Eur J Med Genet. 2020 Jan;63(1):103636. doi: 10.1016/j.ejmg.2019.02.008. Epub 2019 Mar 2.
• [6] Discovery of a frameshift mutation in podocalyxin-like (PODXL) gene, coding for a neural adhesion molecule, as causal for autosomal-recessive juvenile Parkinsonism. J Med Genet. 2016 Jul;53(7):450-6. doi: 10.1136/jmedgenet-2015-103459. Epub 2016 Feb 10.
• [7] 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.
• [8] The influence of neural cell adhesion molecule isoform 140 on the metastasis of thyroid carcinoma.Clin Exp Metastasis. 2013 Mar;30(3):299-307. doi: 10.1007/s10585-012-9537-6. Epub 2012 Sep 27.
• [9] Generation of the induced pluripotent stem cell line, ICAGi002-A, from unaffected carrier megabase scaled duplication involving the CNTN6 gene.Stem Cell Res. 2019 Oct;40:101556. doi: 10.1016/j.scr.2019.101556. Epub 2019 Aug 28.
• [10] GWAS identifies novel SLE susceptibility genes and explains the association of the HLA region.Genes Immun. 2014 Sep;15(6):347-54. doi: 10.1038/gene.2014.23. Epub 2014 May 29.
• [11] 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.
• [12] 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.
• [13] Rare Copy Number Variants in NRXN1 and CNTN6 Increase Risk for Tourette Syndrome. Neuron. 2017 Jun 21;94(6):1101-1111.e7. doi: 10.1016/j.neuron.2017.06.010.
• [14] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [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] 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.
• [17] 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.
• [18] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.