Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTR2V7HO)

• DOT Name: Protein Dok-7 (DOK7)
• Synonyms: Downstream of tyrosine kinase 7
• Gene Name: DOK7
• Related Disease:
  Congenital myasthenic syndrome 10
  Congenital myasthenic syndrome 5
  Acute myelogenous leukaemia
  Congenital myasthenic syndrome
  Esophageal squamous cell carcinoma
  Fetal akinesia deformation sequence 3
  Limb-girdle muscular dystrophy
  Lung cancer
  Lung carcinoma
  Lysosomal lipid storage disorder
  Myopathy
  Neuromuscular disease
  Ptosis
  Congenital muscular dystrophy
  LambertEaton myasthenic syndrome
  Fetal akinesia deformation sequence 1
  Postsynaptic congenital myasthenic syndrome
  Neoplasm
  Asthma
  Breast cancer
  Breast carcinoma
  Myasthenia gravis
• UniProt ID: DOK7_HUMAN
• Pfam ID: PF02174
• Sequence:
  MTEAALVEGQVKLRDGKKWKSRWLVLRKPSPVADCLLMLVYKDKSERIKGLRERSSLTLE
  DICGLEPGLPYEGLVHTLAIVCLSQAIMLGFDSHEAMCAWDARIRYALGEVHRFHVTVAP
  GTKLESGPATLHLCNDVLVLARDIPPAVTGQWKLSDLRRYGAVPSGFIFEGGTRCGYWAG
  VFFLSSAEGEQISFLFDCIVRGISPTKGPFGLRPVLPDPSPPGPSTVEERVAQEALETLQ
  LEKRLSLLSHAGRPGSGGDDRSLSSSSSEASHLDVSASSRLTAWPEQSSSSASTSQEGPR
  PAAAQAAGEAMVGASRPPPKPLRPRQLQEVGRQSSSDSGIATGSHSSYSSSLSSYAGSSL
  DVWRATDELGSLLSLPAAGAPEPSLCTCLPGTVEYQVPTSLRAHYDTPRSLCLAPRDHSP
  PSQGSPGNSAARDSGGQTSAGCPSGWLGTRRRGLVMEAPQGSEATLPGPAPGEPWEAGGP
  HAGPPPAFFSACPVCGGLKVNPPP
• Function: Probable muscle-intrinsic activator of MUSK that plays an essential role in neuromuscular synaptogenesis. Acts in aneural activation of MUSK and subsequent acetylcholine receptor (AchR) clustering in myotubes. Induces autophosphorylation of MUSK.
• Tissue Specificity: Preferentially expressed in skeletal muscle and heart. Present in thigh muscle, diaphragm and heart but not in the liver or spleen (at protein level).

Molecular Interaction Atlas (MIA) of This DOT

22 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Congenital myasthenic syndrome 10	DISQ9F17	Definitive	Autosomal recessive	[1]
Congenital myasthenic syndrome 5	DISJRCI1	Definitive	Biomarker	[2]
Acute myelogenous leukaemia	DISCSPTN	Strong	Altered Expression	[3]
Congenital myasthenic syndrome	DISJLG2T	Strong	Biomarker	[4]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Posttranslational Modification	[5]
Fetal akinesia deformation sequence 3	DISHJZ4P	Strong	Autosomal recessive	[6]
Limb-girdle muscular dystrophy	DISI9Y1Z	Strong	Biomarker	[7]
Lung cancer	DISCM4YA	Strong	Altered Expression	[8]
Lung carcinoma	DISTR26C	Strong	Altered Expression	[8]
Lysosomal lipid storage disorder	DISXQRTX	Strong	Genetic Variation	[9]
Myopathy	DISOWG27	Strong	Biomarker	[10]
Neuromuscular disease	DISQTIJZ	Strong	Altered Expression	[11]
Ptosis	DISJZNIY	Strong	Biomarker	[12]
Congenital muscular dystrophy	DISKY7OY	moderate	Biomarker	[13]
LambertEaton myasthenic syndrome	DISN0Q7Q	moderate	Genetic Variation	[14]
Fetal akinesia deformation sequence 1	DISKDI9L	Supportive	Autosomal recessive	[7]
Postsynaptic congenital myasthenic syndrome	DIS92VN2	Supportive	Autosomal recessive	[15]
Neoplasm	DISZKGEW	Disputed	Altered Expression	[16]
Asthma	DISW9QNS	Limited	Genetic Variation	[17]
Breast cancer	DIS7DPX1	Limited	Altered Expression	[18]
Breast carcinoma	DIS2UE88	Limited	Altered Expression	[18]
Myasthenia gravis	DISELRCI	Limited	Altered Expression	[19]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Protein Dok-7 (DOK7).	[20]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Protein Dok-7 (DOK7).	[26]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Protein Dok-7 (DOK7).	[21]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Protein Dok-7 (DOK7).	[22]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Protein Dok-7 (DOK7).	[23]
Sodium lauryl sulfate	DMLJ634	Approved	Sodium lauryl sulfate increases the expression of Protein Dok-7 (DOK7).	[24]
Ethinyl estradiol	DMODJ40	Approved	Ethinyl estradiol increases the expression of Protein Dok-7 (DOK7).	[25]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of Protein Dok-7 (DOK7).	[23]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Protein Dok-7 (DOK7).	[27]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Protein Dok-7 (DOK7).	[23]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Protein Dok-7 (DOK7).	[28]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane increases the expression of Protein Dok-7 (DOK7).	[29]

References

• [1] 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.
• [2] Beneficial effects of albuterol in congenital endplate acetylcholinesterase deficiency and Dok-7 myasthenia.Muscle Nerve. 2011 Nov;44(5):789-94. doi: 10.1002/mus.22176. Epub 2011 Sep 23.
• [3] Prognostic role of DOK family adapters in acute myeloid leukemia.Cancer Gene Ther. 2019 Sep;26(9-10):305-312. doi: 10.1038/s41417-018-0052-z. Epub 2018 Oct 22.
• [4] Null variants in AGRN cause lethal fetal akinesia deformation sequence.Clin Genet. 2020 Apr;97(4):634-638. doi: 10.1111/cge.13677. Epub 2019 Dec 11.
• [5] Repression of DOK7 mediated by DNMT3A promotes the proliferation and invasion of KYSE410 and TE-12 ESCC cells.Biomed Pharmacother. 2017 Jun;90:93-99. doi: 10.1016/j.biopha.2017.02.111. Epub 2017 Mar 24.
• [6] The muscle protein Dok-7 is essential for neuromuscular synaptogenesis. Science. 2006 Jun 23;312(5781):1802-5. doi: 10.1126/science.1127142.
• [7] Germline mutation in DOK7 associated with fetal akinesia deformation sequence. J Med Genet. 2009 May;46(5):338-40. doi: 10.1136/jmg.2008.065425. Epub 2009 Mar 3.
• [8] DOK7V1 influences the malignant phenotype of lung cancer cells through PI3K/AKT/mTOR and FAK/paxillin signaling pathways.Int J Oncol. 2019 Jan;54(1):381-389. doi: 10.3892/ijo.2018.4624. Epub 2018 Nov 5.
• [9] Phenotype genotype analysis in 15 patients presenting a congenital myasthenic syndrome due to mutations in DOK7.J Neurol. 2010 May;257(5):754-66. doi: 10.1007/s00415-009-5405-y. Epub 2009 Dec 11.
• [10] Genetic and phenotypic characterisation of inherited myopathies in a tertiary neuromuscular centre.Neuromuscul Disord. 2019 Oct;29(10):747-757. doi: 10.1016/j.nmd.2019.08.003. Epub 2019 Aug 19.
• [11] Overexpression of Dok-7 in skeletal muscle enhances neuromuscular transmission with structural alterations of neuromuscular junctions: Implications in robustness of neuromuscular transmission.Biochem Biophys Res Commun. 2020 Feb 26;523(1):214-219. doi: 10.1016/j.bbrc.2019.12.011. Epub 2019 Dec 14.
• [12] Congenital stridor with feeding difficulty as a presenting symptom of Dok7 congenital myasthenic syndrome.Int J Pediatr Otorhinolaryngol. 2010 Sep;74(9):991-4. doi: 10.1016/j.ijporl.2010.05.022. Epub 2010 Jun 15.
• [13] DOK7 limb-girdle myasthenic syndrome mimicking congenital muscular dystrophy.Neuromuscul Disord. 2013 Jan;23(1):36-42. doi: 10.1016/j.nmd.2012.06.355. Epub 2012 Aug 9.
• [14] DOK7 myasthenic syndrome with subacute adult onset during pregnancy and partial response to fluoxetine.Neuromuscul Disord. 2018 Mar;28(3):278-282. doi: 10.1016/j.nmd.2017.12.005. Epub 2017 Dec 13.
• [15] Congenital Myasthenic Syndromes Overview. 2003 May 9 [updated 2021 Dec 23]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews(?) [Internet]. Seattle (WA): University of Washington, Seattle; 1993C2024.
• [16] Repression of Dok7 expression mediated by DNMT1 promotes glioma cells proliferation.Biomed Pharmacother. 2018 Oct;106:678-685. doi: 10.1016/j.biopha.2018.06.156. Epub 2018 Jul 11.
• [17] Effective Treatment With Albuterol in DOK7 Congenital Myasthenic Syndrome in Children.Pediatr Neurol. 2016 Jan;54:85-7. doi: 10.1016/j.pediatrneurol.2015.09.019. Epub 2015 Nov 6.
• [18] The downstream of tyrosine kinase 7 is reduced in lung cancer and is associated with poor survival of patients with lung cancer.Oncol Rep. 2017 May;37(5):2695-2701. doi: 10.3892/or.2017.5538. Epub 2017 Mar 31.
• [19] Silencing of Dok-7 in Adult Rat Muscle Increases Susceptibility to Passive Transfer Myasthenia Gravis.Am J Pathol. 2016 Oct;186(10):2559-68. doi: 10.1016/j.ajpath.2016.05.025.
• [20] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [21] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [22] Retinoic acid receptor alpha amplifications and retinoic acid sensitivity in breast cancers. Clin Breast Cancer. 2013 Oct;13(5):401-8.
• [23] Genistein and bisphenol A exposure cause estrogen receptor 1 to bind thousands of sites in a cell type-specific manner. Genome Res. 2012 Nov;22(11):2153-62.
• [24] CXCL14 downregulation in human keratinocytes is a potential biomarker for a novel in vitro skin sensitization test. Toxicol Appl Pharmacol. 2020 Jan 1;386:114828. doi: 10.1016/j.taap.2019.114828. Epub 2019 Nov 14.
• [25] The genomic response of a human uterine endometrial adenocarcinoma cell line to 17alpha-ethynyl estradiol. Toxicol Sci. 2009 Jan;107(1):40-55.
• [26] 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.
• [27] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [28] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.
• [29] Transcriptome and DNA methylation changes modulated by sulforaphane induce cell cycle arrest, apoptosis, DNA damage, and suppression of proliferation in human liver cancer cells. Food Chem Toxicol. 2020 Feb;136:111047. doi: 10.1016/j.fct.2019.111047. Epub 2019 Dec 12.