Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT48T2ZP)

• DOT Name: Contactin-associated protein-like 2 (CNTNAP2)
• Synonyms: Cell recognition molecule Caspr2
• Gene Name: CNTNAP2
• Related Disease:
  Complex neurodevelopmental disorder
  Cortical dysplasia-focal epilepsy syndrome
  Encephalitis
  Epilepsy
  Glioma
  Neoplasm
  Nervous system disease
  Specific language impairment
  Alcohol dependence
  Alzheimer disease
  Atrial septal defect
  Attention deficit hyperactivity disorder
  Bipolar disorder
  Cerebellar ataxia
  Childhood epilepsy with centrotemporal spikes
  High blood pressure
  Language disorder
  Major depressive disorder
  Mental disorder
  Multiple sclerosis
  Parkinson disease
  Pervasive developmental disorder
  Schizophrenia
  Systemic lupus erythematosus
  Temporal lobe epilepsy
  Tourette syndrome
  Vascular dementia
  Focal epilepsy
  Glaucoma/ocular hypertension
  Neuralgia
  Pitt-Hopkins syndrome
  Psychotic disorder
  Small-cell lung cancer
  Epilepsy syndrome
  Autoimmune disease
  Choreatic disease
  Intellectual disability
• UniProt ID: CNTP2_HUMAN
• PDB ID: 5Y4M
• Pfam ID: PF00754 ; PF02210
• Sequence:
  MQAAPRAGCGAALLLWIVSSCLCRAWTAPSTSQKCDEPLVSGLPHVAFSSSSSISGSYSP
  GYAKINKRGGAGGWSPSDSDHYQWLQVDFGNRKQISAIATQGRYSSSDWVTQYRMLYSDT
  GRNWKPYHQDGNIWAFPGNINSDGVVRHELQHPIIARYVRIVPLDWNGEGRIGLRIEVYG
  CSYWADVINFDGHVVLPYRFRNKKMKTLKDVIALNFKTSESEGVILHGEGQQGDYITLEL
  KKAKLVLSLNLGSNQLGPIYGHTSVMTGSLLDDHHWHSVVIERQGRSINLTLDRSMQHFR
  TNGEFDYLDLDYEITFGGIPFSGKPSSSSRKNFKGCMESINYNGVNITDLARRKKLEPSN
  VGNLSFSCVEPYTVPVFFNATSYLEVPGRLNQDLFSVSFQFRTWNPNGLLVFSHFADNLG
  NVEIDLTESKVGVHINITQTKMSQIDISSGSGLNDGQWHEVRFLAKENFAILTIDGDEAS
  AVRTNSPLQVKTGEKYFFGGFLNQMNNSSHSVLQPSFQGCMQLIQVDDQLVNLYEVAQRK
  PGSFANVSIDMCAIIDRCVPNHCEHGGKCSQTWDSFKCTCDETGYSGATCHNSIYEPSCE
  AYKHLGQTSNYYWIDPDGSGPLGPLKVYCNMTEDKVWTIVSHDLQMQTPVVGYNPEKYSV
  TQLVYSASMDQISAITDSAEYCEQYVSYFCKMSRLLNTPDGSPYTWWVGKANEKHYYWGG
  SGPGIQKCACGIERNCTDPKYYCNCDADYKQWRKDAGFLSYKDHLPVSQVVVGDTDRQGS
  EAKLSVGPLRCQGDRNYWNAASFPNPSSYLHFSTFQGETSADISFYFKTLTPWGVFLENM
  GKEDFIKLELKSATEVSFSFDVGNGPVEIVVRSPTPLNDDQWHRVTAERNVKQASLQVDR
  LPQQIRKAPTEGHTRLELYSQLFVGGAGGQQGFLGCIRSLRMNGVTLDLEERAKVTSGFI
  SGCSGHCTSYGTNCENGGKCLERYHGYSCDCSNTAYDGTFCNKDVGAFFEEGMWLRYNFQ
  APATNARDSSSRVDNAPDQQNSHPDLAQEEIRFSFSTTKAPCILLYISSFTTDFLAVLVK
  PTGSLQIRYNLGGTREPYNIDVDHRNMANGQPHSVNITRHEKTIFLKLDHYPSVSYHLPS
  SSDTLFNSPKSLFLGKVIETGKIDQEIHKYNTPGFTGCLSRVQFNQIAPLKAALRQTNAS
  AHVHIQGELVESNCGASPLTLSPMSSATDPWHLDHLDSASADFPYNPGQGQAIRNGVNRN
  SAIIGGVIAVVIFTILCTLVFLIRYMFRHKGTYHTNEAKGAESAESADAAIMNNDPNFTE
  TIDESKKEWLI
• Function: Required for gap junction formation (Probable). Required, with CNTNAP1, for radial and longitudinal organization of myelinated axons. Plays a role in the formation of functional distinct domains critical for saltatory conduction of nerve impulses in myelinated nerve fibers. Demarcates the juxtaparanodal region of the axo-glial junction.
• Tissue Specificity: Predominantly expressed in nervous system.
• KEGG Pathway: Cell adhesion molecules (hsa04514)

Molecular Interaction Atlas (MIA) of This DOT

37 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Complex neurodevelopmental disorder	DISB9AFI	Definitive	Autosomal recessive	[1]
Cortical dysplasia-focal epilepsy syndrome	DIS47IBV	Definitive	Autosomal recessive	[2]
Encephalitis	DISLD1RL	Definitive	Biomarker	[3]
Epilepsy	DISBB28L	Definitive	Genetic Variation	[4]
Glioma	DIS5RPEH	Definitive	Biomarker	[5]
Neoplasm	DISZKGEW	Definitive	Biomarker	[6]
Nervous system disease	DISJ7GGT	Definitive	Biomarker	[7]
Specific language impairment	DISEKRML	Definitive	Biomarker	[8]
Alcohol dependence	DIS4ZSCO	Strong	Genetic Variation	[9]
Alzheimer disease	DISF8S70	Strong	Genetic Variation	[10]
Atrial septal defect	DISJT76B	Strong	Biomarker	[11]
Attention deficit hyperactivity disorder	DISL8MX9	Strong	Biomarker	[12]
Bipolar disorder	DISAM7J2	Strong	Biomarker	[13]
Cerebellar ataxia	DIS9IRAV	Strong	Biomarker	[14]
Childhood epilepsy with centrotemporal spikes	DISKT2L5	Strong	CausalMutation	[15]
High blood pressure	DISY2OHH	Strong	Genetic Variation	[16]
Language disorder	DISTLKP7	Strong	Altered Expression	[17]
Major depressive disorder	DIS4CL3X	Strong	Biomarker	[18]
Mental disorder	DIS3J5R8	Strong	Genetic Variation	[19]
Multiple sclerosis	DISB2WZI	Strong	Biomarker	[20]
Parkinson disease	DISQVHKL	Strong	Biomarker	[21]
Pervasive developmental disorder	DIS51975	Strong	Biomarker	[22]
Schizophrenia	DISSRV2N	Strong	Genetic Variation	[23]
Systemic lupus erythematosus	DISI1SZ7	Strong	Biomarker	[24]
Temporal lobe epilepsy	DISNOPXX	Strong	Biomarker	[25]
Tourette syndrome	DISX9D54	Strong	Biomarker	[26]
Vascular dementia	DISVO82H	Strong	Genetic Variation	[27]
Focal epilepsy	DIS4LY5L	moderate	Genetic Variation	[28]
Glaucoma/ocular hypertension	DISLBXBY	moderate	Genetic Variation	[29]
Neuralgia	DISWO58J	moderate	Genetic Variation	[30]
Pitt-Hopkins syndrome	DISM1JID	moderate	Altered Expression	[31]
Psychotic disorder	DIS4UQOT	moderate	Genetic Variation	[13]
Small-cell lung cancer	DISK3LZD	moderate	Biomarker	[32]
Epilepsy syndrome	DISLYXJ3	Disputed	Biomarker	[6]
Autoimmune disease	DISORMTM	Limited	Genetic Variation	[6]
Choreatic disease	DISH8K3M	Limited	Biomarker	[33]
Intellectual disability	DISMBNXP	Limited	Genetic Variation	[7]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Cisplatin	DMRHGI9	Approved	Contactin-associated protein-like 2 (CNTNAP2) affects the response to substance of Cisplatin.	[47]

9 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-associated protein-like 2 (CNTNAP2).	[34]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Contactin-associated protein-like 2 (CNTNAP2).	[35]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Contactin-associated protein-like 2 (CNTNAP2).	[36]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Contactin-associated protein-like 2 (CNTNAP2).	[37]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Contactin-associated protein-like 2 (CNTNAP2).	[39]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Contactin-associated protein-like 2 (CNTNAP2).	[40]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Contactin-associated protein-like 2 (CNTNAP2).	[43]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN increases the expression of Contactin-associated protein-like 2 (CNTNAP2).	[45]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Contactin-associated protein-like 2 (CNTNAP2).	[46]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Contactin-associated protein-like 2 (CNTNAP2).	[38]
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the methylation of Contactin-associated protein-like 2 (CNTNAP2).	[41]
Cotinine	DMCEZ1B	Approved	Cotinine affects the methylation of Contactin-associated protein-like 2 (CNTNAP2).	[42]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Contactin-associated protein-like 2 (CNTNAP2).	[44]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Contactin-associated protein-like 2 (CNTNAP2).	[41]

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] Possible case of Pitt-Hopkins syndrome in sibs. Am J Med Genet. 2001 Oct 1;103(2):157-9. doi: 10.1002/ajmg.1523.
• [3] Daratumumab treatment for therapy-refractory anti-CASPR2 encephalitis.J Neurol. 2020 Feb;267(2):317-323. doi: 10.1007/s00415-019-09585-6. Epub 2019 Oct 19.
• [4] Randomized Placebo-Controlled Trial of Intravenous Immunoglobulin in Autoimmune LGI1/CASPR2 Epilepsy.Ann Neurol. 2020 Feb;87(2):313-323. doi: 10.1002/ana.25655. Epub 2019 Dec 14.
• [5] The CASPR2 cell adhesion molecule functions as a tumor suppressor gene in glioma.Oncogene. 2010 Nov 18;29(46):6138-48. doi: 10.1038/onc.2010.342. Epub 2010 Aug 16.
• [6] LGI1 and CASPR2 autoimmunity in children: Systematic literature review and report of a young girl with Morvan syndrome.J Neuroimmunol. 2019 Oct 15;335:577008. doi: 10.1016/j.jneuroim.2019.577008. Epub 2019 Jul 18.
• [7] Disrupted AMPA Receptor Function upon Genetic- or Antibody-Mediated Loss of Autism-Associated CASPR2.Cereb Cortex. 2019 Dec 17;29(12):4919-4931. doi: 10.1093/cercor/bhz032.
• [8] The role of candidate-gene CNTNAP2 in childhood apraxia of speech and specific language impairment.Am J Med Genet B Neuropsychiatr Genet. 2015 Oct;168(7):536-43. doi: 10.1002/ajmg.b.32325. Epub 2015 Jun 19.
• [9] Association of GDNF and CNTNAP2 gene variants with gambling.J Behav Addict. 2019 Sep 1;8(3):471-478. doi: 10.1556/2006.8.2019.40. Epub 2019 Aug 26.
• [10] Genome-wide meta-analysis identifies new loci and functional pathways influencing Alzheimer's disease risk.Nat Genet. 2019 Mar;51(3):404-413. doi: 10.1038/s41588-018-0311-9. Epub 2019 Jan 7.
• [11] Mouse Cntnap2 and Human CNTNAP2 ASD Alleles Cell Autonomously Regulate PV+ Cortical Interneurons.Cereb Cortex. 2018 Nov 1;28(11):3868-3879. doi: 10.1093/cercor/bhx248.
• [12] Cross-species models of attention-deficit/hyperactivity disorder and autism spectrum disorder: lessons from CNTNAP2, ADGRL3, and PARK2.Psychiatr Genet. 2019 Feb;29(1):1-17. doi: 10.1097/YPG.0000000000000211.
• [13] A genome-wide meta-analysis identifies novel loci associated with schizophrenia and bipolar disorder.Schizophr Res. 2010 Dec;124(1-3):192-9. doi: 10.1016/j.schres.2010.09.002.
• [14] Expanding spectrum of contactin-associated protein 2 (CASPR2) autoimmunity-syndrome of parkinsonism and ataxia.Neurol Sci. 2018 Mar;39(3):455-460. doi: 10.1007/s10072-017-3222-0. Epub 2017 Dec 20.
• [15] Exome-wide analysis of mutational burden in patients with typical and atypical Rolandic epilepsy.Eur J Hum Genet. 2018 Feb;26(2):258-264. doi: 10.1038/s41431-017-0034-x. Epub 2018 Jan 22.
• [16] Genetic predictors of glucocorticoid-induced hypertension in children with acute lymphoblastic leukemia.Pharmacogenet Genomics. 2008 Jun;18(6):507-14. doi: 10.1097/FPC.0b013e3282fc5801.
• [17] Associations between the CNTNAP2 gene, dorsolateral prefrontal cortex, and cognitive performance on the Stroop task.Neuroscience. 2017 Feb 20;343:21-29. doi: 10.1016/j.neuroscience.2016.11.021. Epub 2016 Dec 1.
• [18] CNTNAP2 is significantly associated with schizophrenia and major depression in the Han Chinese population.Psychiatry Res. 2013 May 30;207(3):225-8. doi: 10.1016/j.psychres.2012.09.024. Epub 2012 Nov 2.
• [19] Comprehensive cross-disorder analyses of CNTNAP2 suggest it is unlikely to be a primary risk gene for psychiatric disorders.PLoS Genet. 2018 Dec 26;14(12):e1007535. doi: 10.1371/journal.pgen.1007535. eCollection 2018 Dec.
• [20] Differential modulation of the juxtaparanodal complex in Multiple Sclerosis.Mol Cell Neurosci. 2015 Jul;67:93-103. doi: 10.1016/j.mcn.2015.06.005. Epub 2015 Jun 10.
• [21] Identification of candidate genes for Parkinson's disease through blood transcriptome analysis in LRRK2-G2019S carriers, idiopathic cases, and controls.Neurobiol Aging. 2015 Feb;36(2):1105-9. doi: 10.1016/j.neurobiolaging.2014.10.039. Epub 2014 Nov 5.
• [22] Modelling monogenic autism spectrum disorder using mouse cortical organoids.Biochem Biophys Res Commun. 2020 Jan 1;521(1):164-171. doi: 10.1016/j.bbrc.2019.10.097. Epub 2019 Oct 23.
• [23] Genome-wide association study in two populations to determine genetic variants associated with Toxoplasma gondii infection and relationship to schizophrenia risk.Prog Neuropsychopharmacol Biol Psychiatry. 2019 Jun 8;92:133-147. doi: 10.1016/j.pnpbp.2018.12.019. Epub 2019 Jan 2.
• [24] Encephalopathy with upper body hypertonia and myoclonus in patient with systemic lupus erythematosus and anti-CASPR2.Lupus. 2017 Jan;26(1):84-87. doi: 10.1177/0961203316657431. Epub 2016 Jul 17.
• [25] Impact of anti-CASPR2 autoantibodies from patients with autoimmune encephalitis on CASPR2/TAG-1 interaction and Kv1 expression.J Autoimmun. 2019 Sep;103:102284. doi: 10.1016/j.jaut.2019.05.012. Epub 2019 Jun 6.
• [26] Disruption of CNTNAP2 and additional structural genome changes in a boy with speech delay and autism spectrum disorder.Neurogenetics. 2010 Feb;11(1):81-9. doi: 10.1007/s10048-009-0205-1. Epub 2009 Jul 7.
• [27] Genome-wide association analysis of dementia and its clinical endophenotypes reveal novel loci associated with Alzheimer's disease and three causality networks: The GR@ACE project.Alzheimers Dement. 2019 Oct;15(10):1333-1347. doi: 10.1016/j.jalz.2019.06.4950. Epub 2019 Aug 28.
• [28] Cntnap2 Knockout Rats and Mice Exhibit Epileptiform Activity and Abnormal Sleep-Wake Physiology.Sleep. 2017 Jan 1;40(1). doi: 10.1093/sleep/zsw026.
• [29] Efficiently controlling for case-control imbalance and sample relatedness in large-scale genetic association studies.Nat Genet. 2018 Sep;50(9):1335-1341. doi: 10.1038/s41588-018-0184-y. Epub 2018 Aug 13.
• [30] Immune or Genetic-Mediated Disruption of CASPR2 Causes Pain Hypersensitivity Due to Enhanced Primary Afferent Excitability.Neuron. 2018 Feb 21;97(4):806-822.e10. doi: 10.1016/j.neuron.2018.01.033. Epub 2018 Feb 8.
• [31] Functional analysis of TCF4 missense mutations that cause Pitt-Hopkins syndrome.Hum Mutat. 2012 Dec;33(12):1676-86. doi: 10.1002/humu.22160. Epub 2012 Jul 27.
• [32] Comprehensive genomic analysis identifies SOX2 as a frequently amplified gene in small-cell lung cancer.Nat Genet. 2012 Oct;44(10):1111-6. doi: 10.1038/ng.2405. Epub 2012 Sep 2.
• [33] Antibody-associated CNS syndromes without signs of inflammation in the elderly.Neurology. 2017 Oct 3;89(14):1471-1475. doi: 10.1212/WNL.0000000000004541. Epub 2017 Sep 6.
• [34] Design principles of concentration-dependent transcriptome deviations in drug-exposed differentiating stem cells. Chem Res Toxicol. 2014 Mar 17;27(3):408-20.
• [35] 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.
• [36] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [37] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [38] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [39] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [40] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [41] 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.
• [42] 450K epigenome-wide scan identifies differential DNA methylation in newborns related to maternal smoking during pregnancy. Environ Health Perspect. 2012 Oct;120(10):1425-31. doi: 10.1289/ehp.1205412. Epub 2012 Jul 31.
• [43] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [44] 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.
• [45] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [46] 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.
• [47] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.