Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT12DW08)

• DOT Name: Intraflagellar transport protein 172 homolog (IFT172)
• Gene Name: IFT172
• Related Disease:
  Joubert syndrome
  Short-rib thoracic dysplasia 10 with or without polydactyly
  Short-rib thoracic dysplasia 9 with or without polydactyly
  Adult T-cell leukemia/lymphoma
  Ataxia-telangiectasia
  Bardet-Biedl syndrome 20
  Blindness
  Ciliopathy
  Gastrointestinal stromal tumour
  Gout
  Nijmegen breakage syndrome
  Retinitis pigmentosa 71
  T-cell leukaemia
  VACTERL with hydrocephalus
  Vibrio cholerae infection
  Bardet biedl syndrome
  Jeune syndrome
  Retinitis pigmentosa
• UniProt ID: IF172_HUMAN
• Pfam ID: PF00400
• Sequence:
  MHLKHLRTLLSPQDGAAKVTCMAWSQNNAKFAVCTVDRVVLLYDEHGERRDKFSTKPADM
  KYGRKSYMVKGMAFSPDSTKIAIGQTDNIIYVYKIGEDWGDKKVICNKFIQTSAVTCLQW
  PAEYIIVFGLAEGKVRLANTKTNKSSTIYGTESYVVSLTTNCSGKGILSGHADGTIVRYF
  FDDEGSGESQGKLVNHPCPPYALAWATNSIVAAGCDRKIVAYGKEGHMLQTFDYSRDPQE
  REFTTAVSSPGGQSVVLGSYDRLRVFNWIPRRSIWEEAKPKEITNLYTITALAWKRDGSR
  LCVGTLCGGVEQFDCCLRRSIYKNKFELTYVGPSQVIVKNLSSGTRVVLKSHYGYEVEEV
  KILGKERYLVAHTSETLLLGDLNTNRLSEIAWQGSGGNEKYFFENENVCMIFNAGELTLV
  EYGNNDTLGSVRTEFMNPHLISVRINERCQRGTEDNKKLAYLIDIKTIAIVDLIGGYNIG
  TVSHESRVDWLELNETGHKLLFRDRKLRLHLYDIESCSKTMILNFCSYMQWVPGSDVLVA
  QNRNSLCVWYNIEAPERVTMFTIRGDVIGLERGGGKTEVMVMEGVTTVAYTLDEGLIEFG
  TAIDDGNYIRATAFLETLEMTPETEAMWKTLSKLALEARQLHIAERCFSALGQVAKARFL
  HETNEIADQVSREYGGEGTDFYQVRARLAMLEKNYKLAEMIFLEQNAVEEAMGMYQELHR
  WDECIAVAEAKGHPALEKLRRSYYQWLMDTQQEERAGELQESQGDGLAAISLYLKAGLPA
  KAARLVLTREELLANTELVEHITAALIKGELYERAGDLFEKIHNPQKALECYRKGNAFMK
  AVELARLAFPVEVVKLEEAWGDHLVQQKQLDAAINHYIEARCSIKAIEAALGARQWKKAI
  YILDLQDRNTASKYYPLVAQHYASLQEYEIAEELYTKGDRTKDAIDMYTQAGRWEQAHKL
  AMKCMRPEDVSVLYITQAQEMEKQGKYREAERLYVTVQEPDLAITMYKKHKLYDDMIRLV
  GKHHPDLLSDTHLHLGKELEAEGRLQEAEYHYLEAQEWKATVNMYRASGLWEEAYRVART
  QGGANAHKHVAYLWAKSLGGEAAVRLLNKLGLLEAAVDHAADNCSFEFAFELSRLALKHK
  TPEVHLKYAMFLEDEGKFEEAEAEFIRAGKPKEAVLMFVHNQDWEAAQRVAEAHDPDSVA
  EVLVGQARGALEEKDFQKAEGLLLRAQRPGLALNYYKEAGLWSDALRICKDYVPSQLEAL
  QEEYEREATKKGARGVEGFVEQARHWEQAGEYSRAVDCYLKVRDSGNSGLAEKCWMKAAE
  LSIKFLPPQRNMEVVLAVGPQLIGIGKHSAAAELYLNLDLVKEAIDAFIEGEEWNKAKRV
  AKELDPRYEDYVDQHYKEFLKNQGKVDSLVGVDVIAALDLYVEQGQWDKCIETATKQNYK
  ILHKYVALYATHLIREGSSAQALALYVQHGAPANPQNFNIYKRIFTDMVSSPGTNCAEAY
  HSWADLRDVLFNLCENLVKSSEANSPAHEEFKTMLLIAHYYATRSAAQSVKQLETVAARL
  SVSLLRHTQLLPVDKAFYEAGIAAKAVGWDNMAFIFLNRFLDLTDAIEEGTLDGLDHSDF
  QDTDIPFEVPLPAKQHVPEAEREEVRDWVLTVSMDQRLEQVLPRDERGAYEASLVAASTG
  VRALPCLITGYPILRNKIEFKRPGKAANKDNWNKFLMAIKTSHSPVCQDVLKFISQWCGG
  LPSTSFSFQ
• Function: Required for the maintenance and formation of cilia. Plays an indirect role in hedgehog (Hh) signaling, cilia being required for all activity of the hedgehog pathway.
• Reactome Pathway:
  Intraflagellar transport (R-HSA-5620924)
  Hedgehog 'off' state (R-HSA-5610787)

Molecular Interaction Atlas (MIA) of This DOT

18 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Joubert syndrome	DIS7P5CO	Definitive	CausalMutation	[1]
Short-rib thoracic dysplasia 10 with or without polydactyly	DIS9H8HD	Definitive	Autosomal recessive	[2]
Short-rib thoracic dysplasia 9 with or without polydactyly	DISU7SPS	Definitive	Autosomal recessive	[3]
Adult T-cell leukemia/lymphoma	DIS882XU	Strong	Biomarker	[4]
Ataxia-telangiectasia	DISP3EVR	Strong	Biomarker	[3]
Bardet-Biedl syndrome 20	DISXVC6U	Strong	Autosomal recessive	[2]
Blindness	DISTIM10	Strong	Biomarker	[5]
Ciliopathy	DIS10G4I	Strong	Biomarker	[5]
Gastrointestinal stromal tumour	DIS6TJYS	Strong	Biomarker	[6]
Gout	DISHC0U7	Strong	Genetic Variation	[7]
Nijmegen breakage syndrome	DIS98HVL	Strong	Genetic Variation	[8]
Retinitis pigmentosa 71	DISZAAOM	Strong	Autosomal recessive	[2]
T-cell leukaemia	DISJ6YIF	Strong	Biomarker	[4]
VACTERL with hydrocephalus	DISB79CB	Strong	Genetic Variation	[9]
Vibrio cholerae infection	DISW7E3U	Strong	Biomarker	[10]
Bardet biedl syndrome	DISTBNZW	Supportive	Autosomal recessive	[2]
Jeune syndrome	DISLC357	Supportive	Autosomal recessive	[3]
Retinitis pigmentosa	DISCGPY8	Supportive	Autosomal dominant	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Intraflagellar transport protein 172 homolog (IFT172).	[11]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Intraflagellar transport protein 172 homolog (IFT172).	[12]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Intraflagellar transport protein 172 homolog (IFT172).	[13]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Intraflagellar transport protein 172 homolog (IFT172).	[14]
Enzalutamide	DMGL19D	Approved	Enzalutamide affects the expression of Intraflagellar transport protein 172 homolog (IFT172).	[15]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Intraflagellar transport protein 172 homolog (IFT172).	[16]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Intraflagellar transport protein 172 homolog (IFT172).	[17]

References

• [1] Joubert syndrome: a model for untangling recessive disorders with extreme genetic heterogeneity.J Med Genet. 2015 Aug;52(8):514-22. doi: 10.1136/jmedgenet-2015-103087. Epub 2015 Jun 19.
• [2] Mutations in IFT172 cause isolated retinal degeneration and Bardet-Biedl syndrome. Hum Mol Genet. 2015 Jan 1;24(1):230-42. doi: 10.1093/hmg/ddu441. Epub 2014 Aug 28.
• [3] Defects in the IFT-B component IFT172 cause Jeune and Mainzer-Saldino syndromes in humans. Am J Hum Genet. 2013 Nov 7;93(5):915-25. doi: 10.1016/j.ajhg.2013.09.012. Epub 2013 Oct 17.
• [4] Expression of human inducible nitric oxide synthase gene in T-cell lines infected with human T-cell leukemia virus type-I and primary adult T-cell leukemia cells.Blood. 1999 Oct 15;94(8):2862-70.
• [5] Ift172 conditional knock-out mice exhibit rapid retinal degeneration and protein trafficking defects.Hum Mol Genet. 2018 Jun 1;27(11):2012-2024. doi: 10.1093/hmg/ddy109.
• [6] Hedgehog pathway dysregulation contributes to the pathogenesis of human gastrointestinal stromal tumors via GLI-mediated activation of KIT expression. Oncotarget. 2016 Nov 29;7(48):78226-78241. doi: 10.18632/oncotarget.12909.
• [7] Genome-wide association analyses identify 18 new loci associated with serum urate concentrations. Nat Genet. 2013 Feb;45(2):145-54. doi: 10.1038/ng.2500. Epub 2012 Dec 23.
• [8] Identification of a novel mutation confirms the implication of IFT172 (BBS20) in Bardet-Biedl syndrome.J Hum Genet. 2016 May;61(5):447-50. doi: 10.1038/jhg.2015.162. Epub 2016 Jan 14.
• [9] A novel murine allele of Intraflagellar Transport Protein 172 causes a syndrome including VACTERL-like features with hydrocephalus.Hum Mol Genet. 2011 Oct 1;20(19):3725-37. doi: 10.1093/hmg/ddr241. Epub 2011 Jun 8.
• [10] Lipid-Modified Graphene-Transistor Biosensor for Monitoring Amyloid- Aggregation.ACS Appl Mater Interfaces. 2018 Apr 18;10(15):12311-12316. doi: 10.1021/acsami.8b01917. Epub 2018 Apr 5.
• [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] 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.
• [13] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [14] 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.
• [15] NOTCH signaling is activated in and contributes to resistance in enzalutamide-resistant prostate cancer cells. J Biol Chem. 2019 May 24;294(21):8543-8554. doi: 10.1074/jbc.RA118.006983. Epub 2019 Apr 2.
• [16] New insights into BaP-induced toxicity: role of major metabolites in transcriptomics and contribution to hepatocarcinogenesis. Arch Toxicol. 2016 Jun;90(6):1449-58.
• [17] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.