Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT9UQT2S)

• DOT Name: Dysbindin (DTNBP1)
• Synonyms: Biogenesis of lysosome-related organelles complex 1 subunit 8; BLOC-1 subunit 8; Dysbindin-1; Dystrobrevin-binding protein 1; Hermansky-Pudlak syndrome 7 protein; HPS7 protein
• Gene Name: DTNBP1
• Related Disease:
  Hermansky-Pudlak syndrome 7
  Neuroblastoma
  Attention deficit hyperactivity disorder
  Bipolar disorder
  Brain neoplasm
  Cognitive impairment
  Depression
  Duchenne muscular dystrophy
  Hantavirus infection
  Hermansky-Pudlak syndrome
  Major depressive disorder
  Mental disorder
  Mixed anxiety and depressive disorder
  Mood disorder
  Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 4
  Neurodevelopmental disorder
  Neuromuscular disease
  Oculocutaneous albinism
  Panic disorder
  Parkinson disease
  Platelet storage pool deficiency
  Psychotic disorder
  Schizoaffective disorder
  Temporal lobe epilepsy
  Anxiety
  Anxiety disorder
  Autosomal recessive limb-girdle muscular dystrophy type 2H
  Post-traumatic stress disorder
  Bipolar I disorder
  Matthew-Wood syndrome
  Neoplasm
  Nervous system disease
  Opioid dependence
  Pancreatic ductal carcinoma
  Squamous cell carcinoma
• UniProt ID: DTBP1_HUMAN
• Pfam ID: PF04440
• Sequence:
  MLETLRERLLSVQQDFTSGLKTLSDKSREAKVKSKPRTVPFLPKYSAGLELLSRYEDTWA
  ALHRRAKDCASAGELVDSEVVMLSAHWEKKKTSLVELQEQLQQLPALIADLESMTANLTH
  LEASFEEVENNLLHLEDLCGQCELERCKHMQSQQLENYKKNKRKELETFKAELDAEHAQK
  VLEMEHTQQMKLKERQKFFEEAFQQDMEQYLSTGYLQIAERREPIGSMSSMEVNVDMLEQ
  MDLMDISDQEALDVFLNSGGEENTVLSPALGPESSTCQNEITLQVPNPSELRAKPPSSSS
  TCTDSATRDISEGGESPVVQSDEEEVQVDTALATSHTDREATPDGGEDSDS
• Function: Component of the BLOC-1 complex, a complex that is required for normal biogenesis of lysosome-related organelles (LRO), such as platelet dense granules and melanosomes. In concert with the AP-3 complex, the BLOC-1 complex is required to target membrane protein cargos into vesicles assembled at cell bodies for delivery into neurites and nerve terminals. The BLOC-1 complex, in association with SNARE proteins, is also proposed to be involved in neurite extension. Associates with the BLOC-2 complex to facilitate the transport of TYRP1 independent of AP-3 function. Plays a role in synaptic vesicle trafficking and in neurotransmitter release. Plays a role in the regulation of cell surface exposure of DRD2. May play a role in actin cytoskeleton reorganization and neurite outgrowth. May modulate MAPK8 phosphorylation. Appears to promote neuronal transmission and viability through regulating the expression of SNAP25 and SYN1, modulating PI3-kinase-Akt signaling and influencing glutamatergic release. Regulates the expression of SYN1 through binding to its promoter. Modulates prefrontal cortical activity via the dopamine/D2 pathway.
• Tissue Specificity: Detected in brain, in neurons and in neuropil. Isoform 1 is expressed in the cerebral cortex, and hippocampal frontal (HF). Specific expression in the posterior half of the superior temporal gyrus (pSTG). Higher expression of isoform 2 and 3 in the HF than in the pSTG while isoform 1 shows no difference in expression in these areas. In the HF, detected in dentate gyrus (DG) and in pyramidal cells of hippocampus CA2 and CA3 (at protein level). Expressed in all principal neuronal populations of the HF, namely pyramidal neurons in the subiculum and CA1-3, granule cells in the dense cell layer of the DG (DGg), and polymorph cells in the hilus of the DG (DGh). Maximal levels in CA2, CA3, and DGh. Isoform 2 not expressed in the cerebral cortex.
• Reactome Pathway: Golgi Associated Vesicle Biogenesis (R-HSA-432722)

Molecular Interaction Atlas (MIA) of This DOT

35 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hermansky-Pudlak syndrome 7	DIS7WHK0	Definitive	Autosomal recessive	[1]
Neuroblastoma	DISVZBI4	Definitive	Biomarker	[2]
Attention deficit hyperactivity disorder	DISL8MX9	Strong	Biomarker	[3]
Bipolar disorder	DISAM7J2	Strong	Altered Expression	[4]
Brain neoplasm	DISY3EKS	Strong	Biomarker	[5]
Cognitive impairment	DISH2ERD	Strong	Genetic Variation	[6]
Depression	DIS3XJ69	Strong	Biomarker	[7]
Duchenne muscular dystrophy	DISRQ3NV	Strong	Biomarker	[8]
Hantavirus infection	DISZFTMH	Strong	Biomarker	[9]
Hermansky-Pudlak syndrome	DISCY0HQ	Strong	CausalMutation	[10]
Major depressive disorder	DIS4CL3X	Strong	Biomarker	[11]
Mental disorder	DIS3J5R8	Strong	Biomarker	[12]
Mixed anxiety and depressive disorder	DISV809X	Strong	Genetic Variation	[13]
Mood disorder	DISLVMWO	Strong	Genetic Variation	[14]
Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 4	DISGM0K5	Strong	Altered Expression	[15]
Neurodevelopmental disorder	DIS372XH	Strong	Biomarker	[16]
Neuromuscular disease	DISQTIJZ	Strong	Altered Expression	[15]
Oculocutaneous albinism	DISJS7CU	Strong	Biomarker	[17]
Panic disorder	DISD3VNY	Strong	Genetic Variation	[18]
Parkinson disease	DISQVHKL	Strong	Altered Expression	[19]
Platelet storage pool deficiency	DISHODOH	Strong	Biomarker	[17]
Psychotic disorder	DIS4UQOT	Strong	Genetic Variation	[18]
Schizoaffective disorder	DISLBW6B	Strong	Genetic Variation	[7]
Temporal lobe epilepsy	DISNOPXX	Strong	Biomarker	[20]
Anxiety	DISIJDBA	moderate	Biomarker	[21]
Anxiety disorder	DISBI2BT	moderate	Biomarker	[21]
Autosomal recessive limb-girdle muscular dystrophy type 2H	DISZ100M	moderate	Biomarker	[22]
Post-traumatic stress disorder	DISHL1EY	moderate	Genetic Variation	[23]
Bipolar I disorder	DISD09EH	Limited	Genetic Variation	[24]
Matthew-Wood syndrome	DISA7HR7	Limited	Biomarker	[25]
Neoplasm	DISZKGEW	Limited	Altered Expression	[25]
Nervous system disease	DISJ7GGT	Limited	Biomarker	[26]
Opioid dependence	DIS6WEHK	Limited	Biomarker	[12]
Pancreatic ductal carcinoma	DIS26F9Q	Limited	Biomarker	[25]
Squamous cell carcinoma	DISQVIFL	Limited	Genetic Variation	[27]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Clozapine	DMFC71L	Approved	Dysbindin (DTNBP1) increases the response to substance of Clozapine.	[34]
Haloperidol	DM96SE0	Approved	Dysbindin (DTNBP1) increases the response to substance of Haloperidol.	[34]

4 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 Dysbindin (DTNBP1).	[28]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Dysbindin (DTNBP1).	[29]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Dysbindin (DTNBP1).	[30]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Dysbindin (DTNBP1).	[33]

3 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 Dysbindin (DTNBP1).	[31]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Dysbindin (DTNBP1).	[32]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of Dysbindin (DTNBP1).	[32]

References

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• [2] Dysbindin-1, a schizophrenia-related protein, interacts with HDAC3.Neurosci Lett. 2014 Oct 17;582:120-4. doi: 10.1016/j.neulet.2014.08.046. Epub 2014 Sep 6.
• [3] Association of genetic variations in DTNBP1 with cognitive function in schizophrenia patients and healthy subjects.Am J Med Genet B Neuropsychiatr Genet. 2012 Oct;159B(7):841-9. doi: 10.1002/ajmg.b.32091. Epub 2012 Aug 22.
• [4] Antipsychotic drugs attenuate aberrant DNA methylation of DTNBP1 (dysbindin) promoter in saliva and post-mortem brain of patients with schizophrenia and Psychotic bipolar disorder.Am J Med Genet B Neuropsychiatr Genet. 2015 Dec;168(8):687-96. doi: 10.1002/ajmg.b.32361. Epub 2015 Aug 18.
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• [6] Loss of dysbindin-1 affects GABAergic transmission in the PFC.Psychopharmacology (Berl). 2019 Nov;236(11):3291-3300. doi: 10.1007/s00213-019-05285-1. Epub 2019 Jun 14.
• [7] Clinical and molecular genetics of psychotic depression.Schizophr Bull. 2013 Jul;39(4):766-75. doi: 10.1093/schbul/sbt040. Epub 2013 Mar 19.
• [8] Effects of (-)-epicatechin on frontal cortex DAPC and dysbindin of the mdx mice.Neurosci Lett. 2017 Sep 29;658:142-149. doi: 10.1016/j.neulet.2017.08.056.
• [9] Reduced pigmentation (rp), a mouse model of Hermansky-Pudlak syndrome, encodes a novel component of the BLOC-1 complex. Blood. 2004 Nov 15;104(10):3181-9. doi: 10.1182/blood-2004-04-1538. Epub 2004 Jul 20.
• [10] Diagnostic high-throughput sequencing of 2396 patients with bleeding, thrombotic, and platelet disorders.Blood. 2019 Dec 5;134(23):2082-2091. doi: 10.1182/blood.2018891192.
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• [13] Association study of candidate variants from brain-derived neurotrophic factor and dystrobrevin-binding protein 1 with neuroticism, anxiety, and depression.Psychiatr Genet. 2008 Oct;18(5):219-25. doi: 10.1097/YPG.0b013e3283050aee.
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• [15] Dysbindin, syncoilin, and beta-synemin mRNA levels in dystrophic muscles.Int J Neurosci. 2010 Feb;120(2):144-9. doi: 10.3109/00207450903279717.
• [16] Dysbindin Deficiency Modifies the Expression of GABA Neuron and Ion Permeation Transcripts in the Developing Hippocampus.Front Genet. 2017 Mar 10;8:28. doi: 10.3389/fgene.2017.00028. eCollection 2017.
• [17] Clinical and molecular phenotyping of a child with Hermansky-Pudlak syndrome-7, an uncommon genetic type of HPS.Mol Genet Metab. 2017 Apr;120(4):378-383. doi: 10.1016/j.ymgme.2017.02.007. Epub 2017 Feb 27.
• [18] Genetic polymorphism in DTNBP1 gene is associated with methamphetamine-induced panic disorder.J Addict Med. 2014 Nov-Dec;8(6):431-7. doi: 10.1097/ADM.0000000000000075.
• [19] Investigation of the roles of dysbindin-1 and SATB2 in the progression of Parkinson's disease.Eur Rev Med Pharmacol Sci. 2019 Sep;23(17):7510-7516. doi: 10.26355/eurrev_201909_18865.
• [20] Upregulation of dysbindin in temporal lobe epileptic foci of human and experimental animals.Synapse. 2012 Jul;66(7):622-9. doi: 10.1002/syn.21548. Epub 2012 Mar 30.
• [21] Deletion of Dtnbp1 in mice impairs threat memory consolidation and is associated with enhanced inhibitory drive in the amygdala.Transl Psychiatry. 2019 Apr 9;9(1):132. doi: 10.1038/s41398-019-0465-y.
• [22] TRIM32 is an E3 ubiquitin ligase for dysbindin.Hum Mol Genet. 2009 Jul 1;18(13):2344-58. doi: 10.1093/hmg/ddp167. Epub 2009 Apr 6.
• [23] A polymorphism in the dysbindin gene (DTNBP1) associated with multiple psychiatric disorders including schizophrenia.Behav Brain Funct. 2010 Jul 9;6:41. doi: 10.1186/1744-9081-6-41.
• [24] Dysbindin gene variants are associated with bipolar I disorder in a Korean population.Neurosci Lett. 2007 May 18;418(3):272-5. doi: 10.1016/j.neulet.2007.03.037. Epub 2007 Mar 21.
• [25] Dysbindin promotes progression of pancreatic ductal adenocarcinoma via direct activation of PI3K.J Mol Cell Biol. 2017 Dec 1;9(6):504-515. doi: 10.1093/jmcb/mjx043.
• [26] The schizophrenia susceptibility gene dysbindin controls synaptic homeostasis.Science. 2009 Nov 20;326(5956):1127-30. doi: 10.1126/science.1179685.
• [27] Combined analysis of keratinocyte cancers identifies novel genome-wide loci.Hum Mol Genet. 2019 Sep 15;28(18):3148-3160. doi: 10.1093/hmg/ddz121.
• [28] The neuroprotective action of the mood stabilizing drugs lithium chloride and sodium valproate is mediated through the up-regulation of the homeodomain protein Six1. Toxicol Appl Pharmacol. 2009 Feb 15;235(1):124-34.
• [29] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [30] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [31] 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.
• [32] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [33] 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.
• [34] The efficacies of clozapine and haloperidol in refractory schizophrenia are related to DTNBP1 variation. Pharmacogenet Genomics. 2009 Jun;19(6):437-46. doi: 10.1097/FPC.0b013e32832b9cfc.