Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTVBIRH2)

• DOT Name: Dystrobrevin alpha (DTNA)
• Synonyms: DTN-A; Alpha-dystrobrevin; Dystrophin-related protein 3
• Gene Name: DTNA
• Related Disease:
  Autism spectrum disorder
  Barth syndrome
  Becker muscular dystrophy
  Congenital myopathy
  Fetal akinesia deformation sequence 1
  Mitochondrial disease
  Promyelocytic leukaemia
  Congenital muscular dystrophy
  Muscular dystrophy
  Myopathy
  Stroke
  Congenital heart disease
  Dilated cardiomyopathy
  Left ventricular noncompaction
  Left ventricular noncompaction 1
  Meniere disease
• UniProt ID: DTNA_HUMAN
• PDB ID: 2E5R
• Pfam ID: PF09068 ; PF09069 ; PF00569
• Sequence:
  MIEDSGKRGNTMAERRQLFAEMRAQDLDRIRLSTYRTACKLRFVQKKCNLHLVDIWNVIE
  ALRENALNNLDPNTELNVSRLEAVLSTIFYQLNKRMPTTHQIHVEQSISLLLNFLLAAFD
  PEGHGKISVFAVKMALATLCGGKIMDKLRYIFSMISDSSGVMVYGRYDQFLREVLKLPTA
  VFEGPSFGYTEQSARSCFSQQKKVTLNGFLDTLMSDPPPQCLVWLPLLHRLANVENVFHP
  VECSYCHSESMMGFRYRCQQCHNYQLCQDCFWRGHAGGSHSNQHQMKEYTSWKSPAKKLT
  NALSKSLSCASSREPLHPMFPDQPEKPLNLAHIVDTWPPRPVTSMNDTLFSHSVPSSGSP
  FITRSSPPKDSEVEQNKLLARAAPAFLKGKGIQYSLNVADRLADEHVLIGLYVNMLRNNP
  SCMLESSNRLDEEHRLIARYAARLAAESSSSQPPQQRSAPDISFTIDANKQQRQLIAELE
  NKNREILQEIQRLRLEHEQASQPTPEKAQQNPTLLAELRLLRQRKDELEQRMSALQESRR
  ELMVQLEGLMKLLKTQGAGSPRSSPSHTISRPIPMPIRSASACSTPTHTPQDSLTGVGGD
  VQEAFAQSSRRNLRNDLLVAADSITNTMSSLVKELNSEVGSETESNVDSEFARTQFEDLV
  PSPTSEKAFLAQIHARKPGYIHSGATTSTMRGDMVTEDADPYVQPEDENYENDSVRQLEN
  ELQMEEYLKQKLQDEAYQVSLQG
• Function: May be involved in the formation and stability of synapses as well as being involved in the clustering of nicotinic acetylcholine receptors.
• Tissue Specificity: Highly expressed in brain, skeletal and cardiac muscles, and expressed at lower levels in lung, liver and pancreas. Isoform 2 is not expressed in cardiac muscle. Isoform 7 and isoform 8 are only expressed in muscle.
• KEGG Pathway:
  Cytoskeleton in muscle cells (hsa04820)
  Hypertrophic cardiomyopathy (hsa05410)
  Arrhythmogenic right ventricular cardiomyopathy (hsa05412)
  Dilated cardiomyopathy (hsa05414)
  Viral myocarditis (hsa05416)

Molecular Interaction Atlas (MIA) of This DOT

16 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Autism spectrum disorder	DISXK8NV	Strong	Biomarker	[1]
Barth syndrome	DISDI4KU	Strong	Genetic Variation	[2]
Becker muscular dystrophy	DIS5IYHL	Strong	Genetic Variation	[2]
Congenital myopathy	DISLSK9G	Strong	Genetic Variation	[3]
Fetal akinesia deformation sequence 1	DISKDI9L	Strong	Biomarker	[3]
Mitochondrial disease	DISKAHA3	Strong	Genetic Variation	[4]
Promyelocytic leukaemia	DISYGG13	Strong	Biomarker	[5]
Congenital muscular dystrophy	DISKY7OY	moderate	Biomarker	[6]
Muscular dystrophy	DISJD6P7	moderate	Biomarker	[7]
Myopathy	DISOWG27	moderate	Biomarker	[6]
Stroke	DISX6UHX	moderate	Genetic Variation	[8]
Congenital heart disease	DISQBA23	Disputed	Autosomal dominant	[9]
Dilated cardiomyopathy	DISX608J	Limited	Autosomal dominant	[9]
Left ventricular noncompaction	DISJ4QEG	Limited	Genetic Variation	[10]
Left ventricular noncompaction 1	DISE52FL	Limited	Autosomal dominant	[11]
Meniere disease	DISC5R5F	Limited	Autosomal dominant	[11]

16 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 Dystrobrevin alpha (DTNA).	[12]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Dystrobrevin alpha (DTNA).	[13]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Dystrobrevin alpha (DTNA).	[14]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Dystrobrevin alpha (DTNA).	[15]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Dystrobrevin alpha (DTNA).	[16]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Dystrobrevin alpha (DTNA).	[17]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Dystrobrevin alpha (DTNA).	[18]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Dystrobrevin alpha (DTNA).	[19]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Dystrobrevin alpha (DTNA).	[20]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Dystrobrevin alpha (DTNA).	[21]
Ethanol	DMDRQZU	Approved	Ethanol increases the expression of Dystrobrevin alpha (DTNA).	[22]
Malathion	DMXZ84M	Approved	Malathion decreases the expression of Dystrobrevin alpha (DTNA).	[23]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of Dystrobrevin alpha (DTNA).	[26]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Dystrobrevin alpha (DTNA).	[27]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Dystrobrevin alpha (DTNA).	[28]
Coumestrol	DM40TBU	Investigative	Coumestrol decreases the expression of Dystrobrevin alpha (DTNA).	[17]

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 Dystrobrevin alpha (DTNA).	[24]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of Dystrobrevin alpha (DTNA).	[25]

References

• [1] Genotype-phenotype analysis of 18q12.1-q12.2 copy number variation in autism.Eur J Med Genet. 2013 Aug;56(8):420-5. doi: 10.1016/j.ejmg.2013.05.006. Epub 2013 May 29.
• [2] Genetic heterogeneity of left-ventricular noncompaction cardiomyopathy.Clin Cardiol. 2008 May;31(5):201-4. doi: 10.1002/clc.20202.
• [3] Mutations in contactin-1, a neural adhesion and neuromuscular junction protein, cause a familial form of lethal congenital myopathy. Am J Hum Genet. 2008 Dec;83(6):714-24. doi: 10.1016/j.ajhg.2008.10.022. Epub 2008 Nov 20.
• [4] Cardiogenetics, neurogenetics, and pathogenetics of left ventricular hypertrabeculation/noncompaction.Pediatr Cardiol. 2009 Jul;30(5):659-81. doi: 10.1007/s00246-008-9359-0. Epub 2009 Jan 29.
• [5] -Dystrobrevin distribution and association with other proteins in human promyelocytic NB4 cells treated for granulocytic differentiation.Mol Biol Rep. 2011 Jun;38(5):3001-11. doi: 10.1007/s11033-010-9965-9. Epub 2010 Jan 29.
• [6] Deficiency of the syntrophins and alpha-dystrobrevin in patients with inherited myopathy.Neuromuscul Disord. 2003 Aug;13(6):456-67. doi: 10.1016/s0960-8966(03)00066-x.
• [7] The role of -dystrobrevin in striated muscle.Int J Mol Sci. 2011;12(3):1660-71. doi: 10.3390/ijms12031660. Epub 2011 Mar 4.
• [8] Improving Door-to-Needle Times for Acute Ischemic Stroke: Effect of Rapid Patient Registration, Moving Directly to Computed Tomography, and Giving Alteplase at the Computed Tomography Scanner.Circ Cardiovasc Qual Outcomes. 2017 Jan;10(1):e003242. doi: 10.1161/CIRCOUTCOMES.116.003242.
• [9] 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.
• [10] Novel gene mutations in patients with left ventricular noncompaction or Barth syndrome.Circulation. 2001 Mar 6;103(9):1256-63. doi: 10.1161/01.cir.103.9.1256.
• [11] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [12] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [13] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [14] 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.
• [15] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [16] The thioxotriazole copper(II) complex A0 induces endoplasmic reticulum stress and paraptotic death in human cancer cells. J Biol Chem. 2009 Sep 4;284(36):24306-19.
• [17] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [18] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [19] 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.
• [20] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [21] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [22] Effects of acute ethanol treatment on NCCIT cells and NCCIT cell-derived embryoid bodies (EBs). Toxicol In Vitro. 2010 Sep;24(6):1696-704. doi: 10.1016/j.tiv.2010.05.017. Epub 2010 May 26.
• [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] 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.
• [25] 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.
• [26] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [27] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [28] 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.