Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT43AW4H)

• DOT Name: Disrupted in schizophrenia 1 protein (DISC1)
• Gene Name: DISC1
• Related Disease:
  Alzheimer disease
  Anxiety
  Asperger syndrome
  Attention deficit hyperactivity disorder
  Autism
  Autism spectrum disorder
  Behcet disease
  Bipolar depression
  Chondrosarcoma
  Chronic fatigue syndrome
  Classic lissencephaly
  Depression
  Drug dependence
  Huntington disease
  Hyperlipidemia
  Myocardial infarction
  Neurodevelopmental disorder
  Non-small-cell lung cancer
  Progressive multifocal leukoencephalopathy
  Promyelocytic leukaemia
  Psychotic disorder
  Brain disease
  Bronchopulmonary dysplasia
  Influenza
  Intellectual disability
  Mood disorder
  Opioid dependence
  Lissencephaly spectrum disorders
  Nervous system disease
  Anxiety disorder
  Cognitive impairment
  Corpus callosum, agenesis of
  Mental disorder
  Non-insulin dependent diabetes
• UniProt ID: DISC1_HUMAN
• PDB ID: 5V4B
• Sequence:
  MPGGGPQGAPAAAGGGGVSHRAGSRDCLPPAACFRRRRLARRPGYMRSSTGPGIGFLSPA
  VGTLFRFPGGVSGEESHHSESRARQCGLDSRGLLVRSPVSKSAAAPTVTSVRGTSAHFGI
  QLRGGTRLPDRLSWPCGPGSAGWQQEFAAMDSSETLDASWEAACSDGARRVRAAGSLPSA
  ELSSNSCSPGCGPEVPPTPPGSHSAFTSSFSFIRLSLGSAGERGEAEGCPPSREAESHCQ
  SPQEMGAKAASLDGPHEDPRCLSRPFSLLATRVSADLAQAARNSSRPERDMHSLPDMDPG
  SSSSLDPSLAGCGGDGSSGSGDAHSWDTLLRKWEPVLRDCLLRNRRQMEVISLRLKLQKL
  QEDAVENDDYDKAETLQQRLEDLEQEKISLHFQLPSRQPALSSFLGHLAAQVQAALRRGA
  TQQASGDDTHTPLRMEPRLLEPTAQDSLHVSITRRDWLLQEKQQLQKEIEALQARMFVLE
  AKDQQLRREIEEQEQQLQWQGCDLTPLVGQLSLGQLQEVSKALQDTLASAGQIPFHAEPP
  ETIRSLQERIKSLNLSLKEITTKVCMSEKFCSTLRKKVNDIETQLPALLEAKMHAISGNH
  FWTAKDLTEEIRSLTSEREGLEGLLSKLLVLSSRNVKKLGSVKEDYNRLRREVEHQETAY
  ETSVKENTMKYMETLKNKLCSCKCPLLGKVWEADLEACRLLIQSLQLQEARGSLSVEDER
  QMDDLEGAAPPIPPRLHSEDKRKTPLKVLEEWKTHLIPSLHCAGGEQKEESYILSAELGE
  KCEDIGKKLLYLEDQLHTAIHSHDEDLIQSLRRELQMVKETLQAMILQLQPAKEAGEREA
  AASCMTAGVHEAQA
• Function: Involved in the regulation of multiple aspects of embryonic and adult neurogenesis. Required for neural progenitor proliferation in the ventrical/subventrical zone during embryonic brain development and in the adult dentate gyrus of the hippocampus. Participates in the Wnt-mediated neural progenitor proliferation as a positive regulator by modulating GSK3B activity and CTNNB1 abundance. Plays a role as a modulator of the AKT-mTOR signaling pathway controlling the tempo of the process of newborn neurons integration during adult neurogenesis, including neuron positioning, dendritic development and synapse formation. Inhibits the activation of AKT-mTOR signaling upon interaction with CCDC88A. Regulates the migration of early-born granule cell precursors toward the dentate gyrus during the hippocampal development. Inhibits ATF4 transcription factor activity in neurons by disrupting ATF4 dimerization and DNA-binding. Plays a role, together with PCNT, in the microtubule network formation.
• Tissue Specificity: Ubiquitous. Highly expressed in the dentate gyrus of the hippocampus. Also expressed in the temporal and parahippocampal cortices and cells of the white matter.

Molecular Interaction Atlas (MIA) of This DOT

34 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Alzheimer disease	DISF8S70	Strong	Altered Expression	[1]
Anxiety	DISIJDBA	Strong	Biomarker	[2]
Asperger syndrome	DIS7IBSP	Strong	Genetic Variation	[3]
Attention deficit hyperactivity disorder	DISL8MX9	Strong	Altered Expression	[4]
Autism	DISV4V1Z	Strong	Biomarker	[5]
Autism spectrum disorder	DISXK8NV	Strong	Genetic Variation	[6]
Behcet disease	DISSYMBS	Strong	Biomarker	[7]
Bipolar depression	DISA75FU	Strong	Biomarker	[5]
Chondrosarcoma	DIS4I7JB	Strong	Altered Expression	[8]
Chronic fatigue syndrome	DIS34WJ5	Strong	Genetic Variation	[9]
Classic lissencephaly	DISR8S3S	Strong	Biomarker	[10]
Depression	DIS3XJ69	Strong	Genetic Variation	[11]
Drug dependence	DIS9IXRC	Strong	Biomarker	[12]
Huntington disease	DISQPLA4	Strong	Altered Expression	[13]
Hyperlipidemia	DIS61J3S	Strong	Biomarker	[14]
Myocardial infarction	DIS655KI	Strong	Genetic Variation	[14]
Neurodevelopmental disorder	DIS372XH	Strong	Genetic Variation	[15]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[16]
Progressive multifocal leukoencephalopathy	DISX02WS	Strong	Biomarker	[17]
Promyelocytic leukaemia	DISYGG13	Strong	Biomarker	[17]
Psychotic disorder	DIS4UQOT	Strong	Biomarker	[18]
Brain disease	DIS6ZC3X	moderate	Biomarker	[19]
Bronchopulmonary dysplasia	DISO0BY5	moderate	Genetic Variation	[20]
Influenza	DIS3PNU3	moderate	Genetic Variation	[21]
Intellectual disability	DISMBNXP	moderate	Genetic Variation	[22]
Mood disorder	DISLVMWO	moderate	Genetic Variation	[23]
Opioid dependence	DIS6WEHK	moderate	Genetic Variation	[24]
Lissencephaly spectrum disorders	DISBCZL7	Disputed	Genetic Variation	[25]
Nervous system disease	DISJ7GGT	Disputed	Biomarker	[26]
Anxiety disorder	DISBI2BT	Limited	Biomarker	[2]
Cognitive impairment	DISH2ERD	Limited	Altered Expression	[1]
Corpus callosum, agenesis of	DISO9P40	Limited	Genetic Variation	[27]
Mental disorder	DIS3J5R8	Limited	Biomarker	[28]
Non-insulin dependent diabetes	DISK1O5Z	Limited	Biomarker	[29]

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Clozapine	DMFC71L	Approved	Disrupted in schizophrenia 1 protein (DISC1) decreases the response to substance of Clozapine.	[39]
Dextroamphetamine	DMMIHVP	Approved	Disrupted in schizophrenia 1 protein (DISC1) increases the response to substance of Dextroamphetamine.	[40]

9 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 Disrupted in schizophrenia 1 protein (DISC1).	[30]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Disrupted in schizophrenia 1 protein (DISC1).	[31]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Disrupted in schizophrenia 1 protein (DISC1).	[32]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate affects the expression of Disrupted in schizophrenia 1 protein (DISC1).	[33]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Disrupted in schizophrenia 1 protein (DISC1).	[34]
Malathion	DMXZ84M	Approved	Malathion increases the expression of Disrupted in schizophrenia 1 protein (DISC1).	[35]
Permethrin	DMZ0Q1G	Approved	Permethrin increases the expression of Disrupted in schizophrenia 1 protein (DISC1).	[35]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Disrupted in schizophrenia 1 protein (DISC1).	[37]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Disrupted in schizophrenia 1 protein (DISC1).	[30]

2 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 increases the methylation of Disrupted in schizophrenia 1 protein (DISC1).	[36]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the methylation of Disrupted in schizophrenia 1 protein (DISC1).	[38]

References

• [1] Disrupted-in-schizophrenia-1 protects synaptic plasticity in a transgenic mouse model of Alzheimer's disease as a mitophagy receptor.Aging Cell. 2019 Feb;18(1):e12860. doi: 10.1111/acel.12860. Epub 2018 Nov 28.
• [2] Anxiogenic-like behavior and deficient attention/working memory in rats expressing the human DISC1 gene.Pharmacol Biochem Behav. 2019 Apr;179:73-79. doi: 10.1016/j.pbb.2019.02.005. Epub 2019 Feb 16.
• [3] Limited association between Disrupted in Schizophrenia 1 (DISC1) gene and bipolar disorder in the Chinese population.Psychiatr Genet. 2011 Feb;21(1):42-6. doi: 10.1097/ypg.0b013e32834135d2.
• [4] Common and specific genes and peripheral biomarkers in children and adults with attention-deficit/hyperactivity disorder.World J Biol Psychiatry. 2018 Mar;19(2):80-100. doi: 10.1080/15622975.2017.1282175. Epub 2017 Feb 24.
• [5] Disrupted in Schizophrenia 1 forms pathological aggresomes that disrupt its function in intracellular transport.Hum Mol Genet. 2012 May 1;21(9):2017-28. doi: 10.1093/hmg/dds018. Epub 2012 Jan 30.
• [6] Focal Electrographic Seizures in a Patient With Autism Spectrum Disorder and Speech Delay.J Dev Behav Pediatr. 2018 Dec;39(9):763-765. doi: 10.1097/DBP.0000000000000631.
• [7] Primary cilia formation is diminished in schizophrenia and bipolar disorder: A possible marker for these psychiatric diseases.Schizophr Res. 2018 May;195:412-420. doi: 10.1016/j.schres.2017.08.055. Epub 2017 Sep 18.
• [8] Association of Mental Health-Related Proteins DAXX, DRD3, and DISC1 With the Progression and Prognosis of Chondrosarcoma.Front Mol Biosci. 2019 Nov 26;6:134. doi: 10.3389/fmolb.2019.00134. eCollection 2019.
• [9] A functional polymorphism in the disrupted-in schizophrenia 1 gene is associated with chronic fatigue syndrome.Life Sci. 2010 May 8;86(19-20):722-5. doi: 10.1016/j.lfs.2010.03.007. Epub 2010 Mar 20.
• [10] Identification of YWHAE, a gene encoding 14-3-3epsilon, as a possible susceptibility gene for schizophrenia.Hum Mol Genet. 2008 Oct 15;17(20):3212-22. doi: 10.1093/hmg/ddn217. Epub 2008 Jul 24.
• [11] Emerging evidence for the role of pituitary adenylate cyclase-activating peptide in neuropsychiatric disorders.Prog Mol Biol Transl Sci. 2019;167:143-157. doi: 10.1016/bs.pmbts.2019.06.009. Epub 2019 Jul 11.
• [12] Adolescent psychosocial stress enhances sensitization to cocaine exposure in genetically vulnerable mice.Neurosci Res. 2020 Feb;151:38-45. doi: 10.1016/j.neures.2019.02.007. Epub 2019 Mar 1.
• [13] Aggregation of scaffolding protein DISC1 dysregulates phosphodiesterase 4 in Huntington's disease.J Clin Invest. 2017 Apr 3;127(4):1438-1450. doi: 10.1172/JCI85594. Epub 2017 Mar 6.
• [14] Genetic copy number variants in myocardial infarction patients with hyperlipidemia.BMC Genomics. 2011 Nov 30;12 Suppl 3(Suppl 3):S23. doi: 10.1186/1471-2164-12-S3-S23. Epub 2011 Nov 30.
• [15] Endogenous Cell Type-Specific Disrupted in Schizophrenia 1 Interactomes Reveal Protein Networks Associated With Neurodevelopmental Disorders.Biol Psychiatry. 2019 Feb 15;85(4):305-316. doi: 10.1016/j.biopsych.2018.05.009. Epub 2018 May 23.
• [16] DISC1 overexpression promotes non-small cell lung cancer cell proliferation.Oncotarget. 2017 May 22;8(39):65199-65210. doi: 10.18632/oncotarget.18055. eCollection 2017 Sep 12.
• [17] Nuclear DISC1 regulates CRE-mediated gene transcription and sleep homeostasis in the fruit fly.Mol Psychiatry. 2008 Dec;13(12):1138-48, 1069. doi: 10.1038/mp.2008.101. Epub 2008 Sep 2.
• [18] The transcriptome landscape associated with Disrupted-in-Schizophrenia-1 locus impairment in early development and adulthood.Schizophr Res. 2019 Aug;210:149-156. doi: 10.1016/j.schres.2019.05.032. Epub 2019 Jun 13.
• [19] DISC1: a key lead in studying cortical development and associated brain disorders.Neuroscientist. 2013 Oct;19(5):451-64. doi: 10.1177/1073858412470168. Epub 2013 Jan 8.
• [20] DISC1 in adult ADHD patients: an association study in two European samples.Am J Med Genet B Neuropsychiatr Genet. 2013 Apr;162B(3):227-34. doi: 10.1002/ajmg.b.32136. Epub 2013 Feb 6.
• [21] Adolescent Isolation Interacts With DISC1 Point Mutation to Impair Adult Social Memory and Synaptic Functions in the Hippocampus.Front Cell Neurosci. 2018 Aug 2;12:238. doi: 10.3389/fncel.2018.00238. eCollection 2018.
• [22] Rare disruptive variants in the DISC1 Interactome and Regulome: association with cognitive ability and schizophrenia.Mol Psychiatry. 2018 May;23(5):1270-1277. doi: 10.1038/mp.2017.115. Epub 2017 Jun 20.
• [23] DISC1 regulates N-methyl-D-aspartate receptor dynamics: abnormalities induced by a Disc1 mutation modelling a translocation linked to major mental illness.Transl Psychiatry. 2018 Sep 6;8(1):184. doi: 10.1038/s41398-018-0228-1.
• [24] DISC1 as a Possible Genetic Contribution to Opioid Dependence in a Polish Sample.J Stud Alcohol Drugs. 2016 Mar;77(2):220-6. doi: 10.15288/jsad.2016.77.220.
• [25] Does subtle disturbance of neuronal migration contribute to schizophrenia and other neurodevelopmental disorders? Potential genetic mechanisms with possible treatment implications.Eur Neuropsychopharmacol. 2010 May;20(5):281-7. doi: 10.1016/j.euroneuro.2010.02.005. Epub 2010 Mar 5.
• [26] Expression profiles of ndel1a and ndel1b, two orthologs of the NudE-Like gene, in the zebrafish.Gene Expr Patterns. 2007 Jun;7(6):672-9. doi: 10.1016/j.modgep.2007.03.003. Epub 2007 Mar 30.
• [27] Human brain imaging studies of DISC1 in schizophrenia, bipolar disorder and depression: a systematic review.Schizophr Res. 2013 Jun;147(1):1-13. doi: 10.1016/j.schres.2013.03.015. Epub 2013 Apr 16.
• [28] Disrupted in Schizophrenia 1 regulates the processing of reelin in the perinatal cortex.Schizophr Res. 2020 Jan;215:506-513. doi: 10.1016/j.schres.2017.04.012. Epub 2017 Apr 20.
• [29] Beyond the brain: disrupted in schizophrenia 1 regulates pancreatic -cell function via glycogen synthase kinase-3.FASEB J. 2016 Feb;30(2):983-93. doi: 10.1096/fj.15-279810. Epub 2015 Nov 6.
• [30] 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.
• [31] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [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] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [34] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [35] 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.
• [36] 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.
• [37] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [38] 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.
• [39] Association of Disrupted in Schizophrenia 1 (DISC1) missense variants with ultra-resistant schizophrenia. Pharmacogenomics J. 2011 Aug;11(4):267-73. doi: 10.1038/tpj.2010.40. Epub 2010 Jun 8.
• [40] Misassembly of full-length Disrupted-in-Schizophrenia 1 protein is linked to altered dopamine homeostasis and behavioral deficits. Mol Psychiatry. 2016 Nov;21(11):1561-1572. doi: 10.1038/mp.2015.194. Epub 2016 Jan 12.