Details of Drug Off-Target (DOT)

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

• DOT Name: GDNF family receptor alpha-4 (GFRA4)
• Synonyms: GDNF receptor alpha-4; GDNFR-alpha-4; GFR-alpha-4; Persephin receptor
• Gene Name: GFRA4
• Related Disease:
  Hirschsprung disease
  Multiple endocrine neoplasia
  Panic disorder
  Asthma
  Multiple endocrine neoplasia type 2
• UniProt ID: GFRA4_HUMAN
• Pfam ID: PF02351
• Sequence:
  MVRCLGPALLLLLLLGSASSVGGNRCVDAAEACTADARCQRLRSEYVAQCLGRAAQGGCP
  RARCRRALRRFFARGPPALTHALLFCPCAGPACAERRRQTFVPSCAFSGPGPAPPSCLEP
  LNFCERSRVCRCARAAAGPWRGWGRGLSPAHRPPAAQASPPGLSGLVHPSAQRPRRLPAG
  PGRPLPARLRGPRGVPAGTAVTPNYVDNVSARVAPWCDCGASGNRREDCEAFRGLFTRNR
  CLDGAIQAFASGWPPVLLDQLNPQGDPEHSLLQVSSTGRALERRSLLSILPVLALPALL
• Function: Receptor for persephin. Mediates the GDNF-induced autophosphorylation and activation of the RET receptor. May be important in C-cell development and, in the postnatal development of the adrenal medulla.
• Tissue Specificity: Predominantly expressed in the adult thyroid gland. Low levels also found in fetal adrenal and thyroid glands.
• Reactome Pathway:
  RAF/MAP kinase cascade (R-HSA-5673001)
  RET signaling (R-HSA-8853659)
  NCAM1 interactions (R-HSA-419037)

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hirschsprung disease	DISUUSM1	Definitive	Posttranslational Modification	[1]
Multiple endocrine neoplasia	DISZGBKW	Strong	Biomarker	[2]
Panic disorder	DISD3VNY	Strong	Genetic Variation	[3]
Asthma	DISW9QNS	Limited	Biomarker	[4]
Multiple endocrine neoplasia type 2	DISPQ4Y5	Limited	Altered Expression	[5]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Amphotericin B	DMTAJQE	Approved	Amphotericin B increases the expression of GDNF family receptor alpha-4 (GFRA4).	[6]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of GDNF family receptor alpha-4 (GFRA4).	[7]

References

• [1] Demethylation of GFRA4 Promotes Cell Proliferation and Invasion in Hirschsprung Disease.DNA Cell Biol. 2018 Apr;37(4):316-324. doi: 10.1089/dna.2017.3928. Epub 2018 Mar 13.
• [2] A model for GFR alpha 4 function and a potential modifying role in multiple endocrine neoplasia 2.Oncogene. 2005 Feb 3;24(6):1091-7. doi: 10.1038/sj.onc.1207826.
• [3] Whole-exome sequencing and gene-based rare variant association tests suggest that PLA2G4E might be a risk gene for panic disorder.Transl Psychiatry. 2018 Feb 2;8(1):41. doi: 10.1038/s41398-017-0088-0.
• [4] Asthma severity, polymorphisms in 20p13 and their interaction with tobacco smoke exposure.Pediatr Allergy Immunol. 2013 Feb;24(1):10-8. doi: 10.1111/pai.12019.
• [5] Human glial cell line-derived neurotrophic factor receptor alpha 4 is the receptor for persephin and is predominantly expressed in normal and malignant thyroid medullary cells.J Biol Chem. 2001 Mar 23;276(12):9344-51. doi: 10.1074/jbc.M008279200. Epub 2000 Dec 14.
• [6] Differential expression of microRNAs and their predicted targets in renal cells exposed to amphotericin B and its complex with copper (II) ions. Toxicol Mech Methods. 2017 Sep;27(7):537-543. doi: 10.1080/15376516.2017.1333554. Epub 2017 Jun 8.
• [7] Benzo[a]pyrene-induced changes in microRNA-mRNA networks. Chem Res Toxicol. 2012 Apr 16;25(4):838-49.