Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT0G52MC)

• DOT Name: Ectodysplasin-A receptor-associated adapter protein (EDARADD)
• Synonyms: EDAR-associated death domain protein; Protein crinkled homolog
• Gene Name: EDARADD
• Related Disease:
  Ectodermal dysplasia 11A, hypohidrotic/hair/tooth type, autosomal dominant
  Ectodermal dysplasia 11B, hypohidrotic/hair/tooth type, autosomal recessive
  Hypothyroidism
  Incontinentia pigmenti
  Non-insulin dependent diabetes
  Non-small-cell lung cancer
  X-linked hypohidrotic ectodermal dysplasia
  Otitis media
  Autosomal dominant hypohidrotic ectodermal dysplasia
  Autosomal recessive hypohidrotic ectodermal dysplasia
  Tooth agenesis
  Ectodermal dysplasia
• UniProt ID: EDAD_HUMAN
• Pfam ID: PF00531
• Sequence:
  MGLRTTKQMGRGTKAPGHQEDHMVKEPVEDTDPSTLSFNMSDKYPIQDTELPKAEECDTI
  TLNCPRNSDMKNQGEENGFPDSTGDPLPEISKDNSCKENCTCSSCLLRAPTISDLLNDQD
  LLDVIRIKLDPCHPTVKNWRNFASKWGMSYDELCFLEQRPQSPTLEFLLRNSQRTVGQLM
  ELCRLYHRADVEKVLRRWVDEEWPKRERGDPSRHF
• Function: Adapter protein that interacts with EDAR DEATH domain and couples the receptor to EDA signaling pathway during morphogenesis of ectodermal organs. Mediates the activation of NF-kappa-B.
• Tissue Specificity: Detected in adult pancreas, placenta and fetal skin, and at lower levels in lung, thymus, prostate and testis.
• KEGG Pathway: NF-kappa B sig.ling pathway (hsa04064)
• Reactome Pathway: TNFs bind their physiological receptors (R-HSA-5669034)

Molecular Interaction Atlas (MIA) of This DOT

12 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Ectodermal dysplasia 11A, hypohidrotic/hair/tooth type, autosomal dominant	DIS9IAMU	Strong	Autosomal dominant	[1]
Ectodermal dysplasia 11B, hypohidrotic/hair/tooth type, autosomal recessive	DISLO9AA	Strong	Autosomal recessive	[1]
Hypothyroidism	DISR0H6D	Strong	Genetic Variation	[2]
Incontinentia pigmenti	DIS0ALLE	Strong	Genetic Variation	[3]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Genetic Variation	[4]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Posttranslational Modification	[5]
X-linked hypohidrotic ectodermal dysplasia	DISST0XM	Strong	Genetic Variation	[6]
Otitis media	DISGZDUO	moderate	Biomarker	[7]
Autosomal dominant hypohidrotic ectodermal dysplasia	DISGWW7F	Supportive	Autosomal dominant	[8]
Autosomal recessive hypohidrotic ectodermal dysplasia	DISGAO5V	Supportive	Autosomal recessive	[8]
Tooth agenesis	DIS1PWC7	Supportive	Autosomal dominant	[8]
Ectodermal dysplasia	DISLRS4M	Limited	Genetic Variation	[3]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Ectodysplasin-A receptor-associated adapter protein (EDARADD).	[9]
Bortezomib	DMNO38U	Approved	Bortezomib increases the expression of Ectodysplasin-A receptor-associated adapter protein (EDARADD).	[10]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Ectodysplasin-A receptor-associated adapter protein (EDARADD).	[11]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Ectodysplasin-A receptor-associated adapter protein (EDARADD).	[13]

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 affects the methylation of Ectodysplasin-A receptor-associated adapter protein (EDARADD).	[12]

References

• [1] Gene defect in ectodermal dysplasia implicates a death domain adapter in development. Nature. 2001 Dec 20-27;414(6866):913-6. doi: 10.1038/414913a.
• [2] Leveraging Polygenic Functional Enrichment to Improve GWAS Power.Am J Hum Genet. 2019 Jan 3;104(1):65-75. doi: 10.1016/j.ajhg.2018.11.008. Epub 2018 Dec 27.
• [3] From ectodermal dysplasia to selective tooth agenesis.Am J Med Genet A. 2009 Sep;149A(9):2037-41. doi: 10.1002/ajmg.a.32801.
• [4] Genetic Variants in HSD17B3, SMAD3, and IPO11 Impact Circulating Lipids in Response to Fenofibrate in Individuals With Type 2 Diabetes.Clin Pharmacol Ther. 2018 Apr;103(4):712-721. doi: 10.1002/cpt.798. Epub 2017 Nov 3.
• [5] Aberrant DNA methylation in non-small cell lung cancer-associated fibroblasts.Carcinogenesis. 2015 Dec;36(12):1453-63. doi: 10.1093/carcin/bgv146. Epub 2015 Oct 7.
• [6] A novel missense mutation in the gene EDARADD associated with an unusual phenotype of hypohidrotic ectodermal dysplasia.Am J Med Genet A. 2016 Jan;170A(1):249-53. doi: 10.1002/ajmg.a.37412. Epub 2015 Oct 5.
• [7] Role of ectodysplasin signalling in middle ear and nasal pathology in rat and mouse models of hypohidrotic ectodermal dysplasia.Dis Model Mech. 2019 Apr 25;12(4):dmm037804. doi: 10.1242/dmm.037804.
• [8] Clinical Practice Guidelines for Rare Diseases: The Orphanet Database. PLoS One. 2017 Jan 18;12(1):e0170365. doi: 10.1371/journal.pone.0170365. eCollection 2017.
• [9] 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.
• [10] Induction of heme oxygenase-1 by cobalt protoporphyrin enhances the antitumour effect of bortezomib in adult T-cell leukaemia cells. Br J Cancer. 2007 Oct 22;97(8):1099-105. doi: 10.1038/sj.bjc.6604003. Epub 2007 Sep 25.
• [11] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [12] 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.
• [13] Synergistic effect of JQ1 and rapamycin for treatment of human osteosarcoma. Int J Cancer. 2015 May 1;136(9):2055-64.