Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTMH0MBI)

• DOT Name: Intraflagellar transport protein 80 homolog (IFT80)
• Synonyms: WD repeat-containing protein 56
• Gene Name: IFT80
• Related Disease:
  Asphyxiating thoracic dystrophy 2
  Asphyxiating thoracic dystrophy 3
  Ataxia-telangiectasia
  Bloom syndrome
  Bone development disease
  Ciliopathy
  Epithelial ovarian cancer
  MHC class II deficiency
  Ovarian cancer
  Ovarian neoplasm
  Polydactyly
  Respiratory failure
  Retinal degeneration
  Short rib dysplasia
  Short rib-polydactyly syndrome
  Fetal growth restriction
  Beemer-Langer syndrome
  Jeune syndrome
  Obsolete short rib-polydactyly syndrome, Verma-Naumoff type
  Gastric cancer
  Stomach cancer
• UniProt ID: IFT80_HUMAN
• Pfam ID: PF00400
• Sequence:
  MRLKISLLKEPKHQELVSCVGWTTAEELYSCSDDHQIVKWNLLTSETTQIVKLPDDIYPI
  DFHWFPKSLGVKKQTQAESFVLTSSDGKFHLISKLGRVEKSVEAHCGAVLAGRWNYEGTA
  LVTVGEDGQIKIWSKTGMLRSTLAQQGTPVYSVAWGPDSEKVLYTAGKQLIIKPLQPNAK
  VLQWKAHDGIILKVDWNSVNDLILSAGEDCKYKVWDSYGRPLYNSQPHEHPITSVAWAPD
  GELFAVGSFHTLRLCDKTGWSYALEKPNTGSIFNIAWSIDGTQIAGACGNGHVVFAHVVE
  QHWEWKNFQVTLTKRRAMQVRNVLNDAVDLLEFRDRVIKASLNYAHLVVSTSLQCYVFST
  KNWNTPIIFDLKEGTVSLILQAERHFLLVDGSSIYLYSYEGRFISSPKFPGMRTDILNAQ
  TVSLSNDTIAIRDKADEKIIFLFEASTGKPLGDGKFLSHKNEILEIALDQKGLTNDRKIA
  FIDKNRDLCITSVKRFGKEEQIIKLGTMVHTLAWNDTCNILCGLQDTRFIVWYYPNTVYV
  DRDILPKTLYERDASEFSKNPHIVSFVGNQVTIRRADGSLVHISITPYPAILHEYVSSSK
  WEDAVRLCRFVKEQTMWACLAAMAVANRDMTTAEIAYAAIGEIDKVQYINSIKNLPSKES
  KMAHILLFSGNIQEAEIVLLQAGLVYQAIQININLYNWERALELAVKYKTHVDTVLAYRQ
  KFLETFGKQETNKRYLHYAEGLQIDWEKIKAKIEMEITKEREQSSSSQSSKSIGLKP
• Function: Component of the intraflagellar transport (IFT) complex B, which is essential for the development and maintenance of motile and sensory cilia.
• Tissue Specificity: Isoform IFT80-L is widely expressed.
• Reactome Pathway: Intraflagellar transport (R-HSA-5620924)

Molecular Interaction Atlas (MIA) of This DOT

21 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Asphyxiating thoracic dystrophy 2	DIS115TB	Definitive	Autosomal recessive	[1]
Asphyxiating thoracic dystrophy 3	DISFN8TK	Strong	Biomarker	[2]
Ataxia-telangiectasia	DISP3EVR	Strong	Biomarker	[3]
Bloom syndrome	DISKXQ7J	Strong	Genetic Variation	[4]
Bone development disease	DISVKAZS	Strong	Biomarker	[1]
Ciliopathy	DIS10G4I	Strong	Genetic Variation	[4]
Epithelial ovarian cancer	DIS56MH2	Strong	Altered Expression	[5]
MHC class II deficiency	DISWMI0G	Strong	Genetic Variation	[4]
Ovarian cancer	DISZJHAP	Strong	Altered Expression	[5]
Ovarian neoplasm	DISEAFTY	Strong	Altered Expression	[5]
Polydactyly	DIS25BMZ	Strong	Biomarker	[1]
Respiratory failure	DISVMYJO	Strong	Biomarker	[1]
Retinal degeneration	DISM1JHQ	Strong	Biomarker	[1]
Short rib dysplasia	DISRBNBF	Strong	Biomarker	[2]
Short rib-polydactyly syndrome	DISY2RES	Strong	Biomarker	[2]
Fetal growth restriction	DIS5WEJ5	moderate	Altered Expression	[6]
Beemer-Langer syndrome	DIS3TBQE	Supportive	Autosomal recessive	[4]
Jeune syndrome	DISLC357	Supportive	Autosomal recessive	[1]
Obsolete short rib-polydactyly syndrome, Verma-Naumoff type	DISS6UQH	Supportive	Autosomal recessive	[7]
Gastric cancer	DISXGOUK	Limited	Biomarker	[8]
Stomach cancer	DISKIJSX	Limited	Biomarker	[8]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Intraflagellar transport protein 80 homolog (IFT80).	[9]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Intraflagellar transport protein 80 homolog (IFT80).	[14]

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 Intraflagellar transport protein 80 homolog (IFT80).	[10]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Intraflagellar transport protein 80 homolog (IFT80).	[11]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Intraflagellar transport protein 80 homolog (IFT80).	[12]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Intraflagellar transport protein 80 homolog (IFT80).	[13]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Intraflagellar transport protein 80 homolog (IFT80).	[15]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Intraflagellar transport protein 80 homolog (IFT80).	[16]
Clorgyline	DMCEUJD	Approved	Clorgyline increases the expression of Intraflagellar transport protein 80 homolog (IFT80).	[17]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Intraflagellar transport protein 80 homolog (IFT80).	[18]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Intraflagellar transport protein 80 homolog (IFT80).	[19]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of Intraflagellar transport protein 80 homolog (IFT80).	[20]

References

• [1] IFT80, which encodes a conserved intraflagellar transport protein, is mutated in Jeune asphyxiating thoracic dystrophy. Nat Genet. 2007 Jun;39(6):727-9. doi: 10.1038/ng2038. Epub 2007 Apr 29.
• [2] An Ift80 mouse model of short rib polydactyly syndromes shows defects in hedgehog signalling without loss or malformation of cilia.Hum Mol Genet. 2011 Apr 1;20(7):1306-14. doi: 10.1093/hmg/ddr013. Epub 2011 Jan 12.
• [3] DYNC2H1 mutations cause asphyxiating thoracic dystrophy and short rib-polydactyly syndrome, type III.Am J Hum Genet. 2009 May;84(5):706-11. doi: 10.1016/j.ajhg.2009.04.016.
• [4] Mutations in IFT80 cause SRPS Type IV. Report of two families and review. Am J Med Genet A. 2019 Apr;179(4):639-644. doi: 10.1002/ajmg.a.61050. Epub 2019 Feb 14.
• [5] ATAD2 predicts poor outcomes in patients with ovarian cancer and is a marker of proliferation.Int J Oncol. 2020 Jan;56(1):219-231. doi: 10.3892/ijo.2019.4913. Epub 2019 Nov 14.
• [6] iTRAQ-Based Proteomic Analysis of Neonatal Kidney from Offspring of Protein Restricted Rats Reveals Abnormalities in Intraflagellar Transport Proteins.Cell Physiol Biochem. 2017;44(1):185-199. doi: 10.1159/000484626. Epub 2017 Nov 6.
• [7] Ciliary disorder of the skeleton. Am J Med Genet C Semin Med Genet. 2012 Aug 15;160C(3):165-74. doi: 10.1002/ajmg.c.31336. Epub 2012 Jul 12.
• [8] IFT80 Improves Invasion Ability in Gastric Cancer Cell Line via ift80/p75NGFR/MMP9 Signaling.Int J Mol Sci. 2018 Nov 16;19(11):3616. doi: 10.3390/ijms19113616.
• [9] 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.
• [10] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [11] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [12] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [13] 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.
• [14] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [15] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [16] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [17] Anti-oncogenic and pro-differentiation effects of clorgyline, a monoamine oxidase A inhibitor, on high grade prostate cancer cells. BMC Med Genomics. 2009 Aug 20;2:55. doi: 10.1186/1755-8794-2-55.
• [18] 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.
• [19] 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.
• [20] A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.