Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT6QBA05)

• DOT Name: Dystroglycan 1 (DAG1)
• Synonyms: Dystroglycan; Dystrophin-associated glycoprotein 1
• Gene Name: DAG1
• Related Disease:
  Autosomal recessive limb-girdle muscular dystrophy type 2P
  Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A9
  Muscular dystrophy-dystroglycanopathy, type A
• UniProt ID: DAG1_HUMAN
• PDB ID: 1EG4; 2MK7; 5GGP; 5LLK; 6JJY; 7E9K; 7E9L
• Pfam ID: PF18424 ; PF05454 ; PF05345
• Sequence:
  MRMSVGLSLLLPLSGRTFLLLLSVVMAQSHWPSEPSEAVRDWENQLEASMHSVLSDLHEA
  VPTVVGIPDGTAVVGRSFRVTIPTDLIASSGDIIKVSAAGKEALPSWLHWDSQSHTLEGL
  PLDTDKGVHYISVSATRLGANGSHIPQTSSVFSIEVYPEDHSELQSVRTASPDPGEVVSS
  ACAADEPVTVLTVILDADLTKMTPKQRIDLLHRMRSFSEVELHNMKLVPVVNNRLFDMSA
  FMAGPGNAKKVVENGALLSWKLGCSLNQNSVPDIHGVEAPAREGAMSAQLGYPVVGWHIA
  NKKPPLPKRVRRQIHATPTPVTAIGPPTTAIQEPPSRIVPTPTSPAIAPPTETMAPPVRD
  PVPGKPTVTIRTRGAIIQTPTLGPIQPTRVSEAGTTVPGQIRPTMTIPGYVEPTAVATPP
  TTTTKKPRVSTPKPATPSTDSTTTTTRRPTKKPRTPRPVPRVTTKVSITRLETASPPTRI
  RTTTSGVPRGGEPNQRPELKNHIDRVDAWVGTYFEVKIPSDTFYDHEDTTTDKLKLTLKL
  REQQLVGEKSWVQFNSNSQLMYGLPDSSHVGKHEYFMHATDKGGLSAVDAFEIHVHRRPQ
  GDRAPARFKAKFVGDPALVLNDIHKKIALVKKLAFAFGDRNCSTITLQNITRGSIVVEWT
  NNTLPLEPCPKEQIAGLSRRIAEDDGKPRPAFSNALEPDFKATSITVTGSGSCRHLQFIP
  VVPPRRVPSEAPPTEVPDRDPEKSSEDDVYLHTVIPAVVVAAILLIAGIIAMICYRKKRK
  GKLTLEDQATFIKKGVPIIFADELDDSKPPPSSSMPLILQEEKAPLPPPEYPNQSVPETT
  PLNQDTMGEYTPLRDEDPNAPPYQPPPPFTAPMEGKGSRPKNMTPYRSPPPYVPP
• Function: The dystroglycan complex is involved in a number of processes including laminin and basement membrane assembly, sarcolemmal stability, cell survival, peripheral nerve myelination, nodal structure, cell migration, and epithelial polarization.; [Alpha-dystroglycan]: Extracellular peripheral glycoprotein that acts as a receptor for extracellular matrix proteins containing laminin-G domains. Receptor for laminin-2 (LAMA2) and agrin in peripheral nerve Schwann cells. Also acts as a receptor for laminin LAMA5; [Beta-dystroglycan]: Transmembrane protein that plays important roles in connecting the extracellular matrix to the cytoskeleton. Acts as a cell adhesion receptor in both muscle and non-muscle tissues. Receptor for both DMD and UTRN and, through these interactions, scaffolds axin to the cytoskeleton. Also functions in cell adhesion-mediated signaling and implicated in cell polarity.; [Alpha-dystroglycan]: (Microbial infection) Acts as a receptor for lassa virus and lymphocytic choriomeningitis virus glycoprotein and class C new-world arenaviruses. Acts as a Schwann cell receptor for Mycobacterium leprae, the causative organism of leprosy, but only in the presence of the G-domain of LAMA2.
• Tissue Specificity: Expressed in a variety of fetal and adult tissues. In epidermal tissue, located to the basement membrane. Also expressed in keratinocytes and fibroblasts.
• KEGG Pathway:
  ECM-receptor interaction (hsa04512)
  Cytoskeleton in muscle cells (hsa04820)
  Hypertrophic cardiomyopathy (hsa05410)
  Arrhythmogenic right ventricular cardiomyopathy (hsa05412)
  Dilated cardiomyopathy (hsa05414)
  Viral myocarditis (hsa05416)
• Reactome Pathway:
  ECM proteoglycans (R-HSA-3000178)
  Defective POMGNT1 causes MDDGA3, MDDGB3 and MDDGC3 (R-HSA-5083628)
  Defective POMT2 causes MDDGA2, MDDGB2 and MDDGC2 (R-HSA-5083629)
  Defective POMT1 causes MDDGA1, MDDGB1 and MDDGC1 (R-HSA-5083633)
  O-linked glycosylation (R-HSA-5173105)
  Regulation of expression of SLITs and ROBOs (R-HSA-9010553)
  EGR2 and SOX10-mediated initiation of Schwann cell myelination (R-HSA-9619665)
  Non-integrin membrane-ECM interactions (R-HSA-3000171)

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Autosomal recessive limb-girdle muscular dystrophy type 2P	DIS9NZDO	Definitive	Autosomal recessive	[1]
Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A9	DISPSGSK	Definitive	Autosomal recessive	[1]
Muscular dystrophy-dystroglycanopathy, type A	DISZTBC4	Supportive	Autosomal recessive	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Dystroglycan 1 (DAG1) affects the response to substance of Doxorubicin.	[13]
Isoproterenol	DMK7MEY	Approved	Dystroglycan 1 (DAG1) increases the Apoptosis ADR of Isoproterenol.	[14]

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 Dystroglycan 1 (DAG1).	[3]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Dystroglycan 1 (DAG1).	[4]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Dystroglycan 1 (DAG1).	[5]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Dystroglycan 1 (DAG1).	[6]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Dystroglycan 1 (DAG1).	[7]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Dystroglycan 1 (DAG1).	[8]
Marinol	DM70IK5	Approved	Marinol increases the expression of Dystroglycan 1 (DAG1).	[9]
Resveratrol	DM3RWXL	Phase 3	Resveratrol decreases the expression of Dystroglycan 1 (DAG1).	[10]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Dystroglycan 1 (DAG1).	[12]

1 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 decreases the methylation of Dystroglycan 1 (DAG1).	[11]

References

• [1] A dystroglycan mutation associated with limb-girdle muscular dystrophy. N Engl J Med. 2011 Mar 10;364(10):939-46. doi: 10.1056/NEJMoa1006939.
• [2] Absence of - and -dystroglycan is associated with Walker-Warburg syndrome. Neurology. 2015 May 26;84(21):2177-82. doi: 10.1212/WNL.0000000000001615. Epub 2015 May 1.
• [3] 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.
• [4] 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.
• [5] Systems analysis of transcriptome and proteome in retinoic acid/arsenic trioxide-induced cell differentiation/apoptosis of promyelocytic leukemia. Proc Natl Acad Sci U S A. 2005 May 24;102(21):7653-8.
• [6] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [7] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [8] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [9] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
• [10] Molecular mechanisms of resveratrol action in lung cancer cells using dual protein and microarray analyses. Cancer Res. 2007 Dec 15;67(24):12007-17. doi: 10.1158/0008-5472.CAN-07-2464.
• [11] 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.
• [12] 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.
• [13] 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.
• [14] ADReCS-Target: target profiles for aiding drug safety research and application. Nucleic Acids Res. 2018 Jan 4;46(D1):D911-D917. doi: 10.1093/nar/gkx899.