Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT6KO5FH)

• DOT Name: Intraflagellar transport protein 140 homolog (IFT140)
• Synonyms: WD and tetratricopeptide repeats protein 2
• Gene Name: IFT140
• Related Disease:
  Autosomal dominant polycystic kidney disease
  IFT140-related recessive ciliopathy
  Short-rib thoracic dysplasia 9 with or without polydactyly
  Ciliopathy
  Inherited retinal dystrophy
  Leber congenital amaurosis 1
  Male infertility
  Marinesco-Sjogren syndrome
  Polycystic kidney disease
  Retinitis pigmentosa 80
  Short rib dysplasia
  C syndrome
  Nephronophthisis
  Jeune syndrome
  Leber congenital amaurosis
  Retinitis pigmentosa
  Infertility
  Meckel syndrome, type 1
  Nephropathy
• UniProt ID: IF140_HUMAN
• PDB ID: 8BBF; 8BBG; 8FGW; 8FH3
• Sequence:
  MALYYDHQIEAPDAAGSPSFISWHPVHPFLAVAYISTTSTGSVDIYLEQGECVPDTHVER
  PFRVASLCWHPTRLVLAVGWETGEVTVFNKQDKEQHTMPLTHTADITVLRWSPSGNCLLS
  GDRLGVLLLWRLDQRGRVQGTPLLKHEYGKHLTHCIFRLPPPGEDLVQLAKAAVSGDEKA
  LDMFNWKKSSSGSLLKMGSHEGLLFFVSLMDGTVHYVDEKGKTTQVVSADSTIQMLFYME
  KREALVVVTENLRLSLYTVPPEGKAEEVMKVKLSGKTGRRADIALIEGSLLVMAVGEAAL
  RFWDIERGENYILSPDEKFGFEKGENMNCVCYCKVKGLLAAGTDRGRVAMWRKVPDFLGS
  PGAEGKDRWALQTPTELQGNITQIQWGSRKNLLAVNSVISVAILSERAMSSHFHQQVAAM
  QVSPSLLNVCFLSTGVAHSLRTDMHISGVFATKDAVAVWNGRQVAIFELSGAAIRSAGTF
  LCETPVLAMHEENVYTVESNRVQVRTWQGTVKQLLLFSETEGNPCFLDICGNFLVVGTDL
  AHFKSFDLSRREAKAHCSCRSLAELVPGVGGIASLRCSSSGSTISILPSKADNSPDSKIC
  FYDVEMDTVTVFDFKTGQIDRRETLSFNEQETNKSHLFVDEGLKNYVPVNHFWDQSEPRL
  FVCEAVQETPRSQPQSANGQPQDGRAGPAADVLILSFFISEEHGFLLHESFPRPATSHSL
  LGMEVPYYYFTRKPEEADREDEVEPGCHHIPQMVSRRPLRDFVGLEDCDKATRDAMLHFS
  FFVTIGDMDEAFKSIKLIKSEAVWENMARMCVKTQRLDVAKVCLGNMGHARGARALREAE
  QEPELEARVAVLATQLGMLEDAEQLYRKCKRHDLLNKFYQAAGRWQEALQVAEHHDRVHL
  RSTYHRYAGHLEASADCSRALSYYEKSDTHRFEVPRMLSEDLPSLELYVNKMKDKTLWRW
  WAQYLESQGEMDAALHYYELARDHFSLVRIHCFQGNVQKAAQIANETGNLAASYHLARQY
  ESQEEVGQAVHFYTRAQAFKNAIRLCKENGLDDQLMNLALLSSPEDMIEAARYYEEKGVQ
  MDRAVMLYHKAGHFSKALELAFATQQFVALQLIAEDLDETSDPALLARCSDFFIEHSQYE
  RAVELLLAARKYQEALQLCLGQNMSITEEMAEKMTVAKDSSDLPEESRRELLEQIADCCM
  RQGSYHLATKKYTQAGNKLKAMRALLKSGDTEKITFFASVSRQKEIYIMAANYLQSLDWR
  KEPEIMKNIIGFYTKGRALDLLAGFYDACAQVEIDEYQNYDKAHGALTEAYKCLAKAKAK
  SPLDQETRLAQLQSRMALVKRFIQARRTYTEDPKESIKQCELLLEEPDLDSTIRIGDVYG
  FLVEHYVRKEEYQTAYRFLEEMRRRLPLANMSYYVSPQAVDAVHRGLGLPLPRTVPEQVR
  HNSMEDARELDEEVVEEADDDP
• Function: Component of the IFT complex A (IFT-A), a complex required for retrograde ciliary transport and entry into cilia of G protein-coupled receptors (GPCRs). Plays a pivotal role in proper development and function of ciliated cells through its role in ciliogenesis and/or cilium maintenance. Required for the development and maintenance of the outer segments of rod and cone photoreceptor cells. Plays a role in maintenance and the delivery of opsin to the outer segment of photoreceptor cells.
• Reactome Pathway:
  Intraflagellar transport (R-HSA-5620924)
  Hedgehog 'off' state (R-HSA-5610787)

Molecular Interaction Atlas (MIA) of This DOT

19 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Autosomal dominant polycystic kidney disease	DISBHWUI	Definitive	Autosomal dominant	[1]
IFT140-related recessive ciliopathy	DISKDRMB	Definitive	Autosomal recessive	[1]
Short-rib thoracic dysplasia 9 with or without polydactyly	DISU7SPS	Definitive	Autosomal recessive	[2]
Ciliopathy	DIS10G4I	Strong	Biomarker	[3]
Inherited retinal dystrophy	DISGGL77	Strong	Genetic Variation	[4]
Leber congenital amaurosis 1	DISY2B33	Strong	Genetic Variation	[5]
Male infertility	DISY3YZZ	Strong	Genetic Variation	[3]
Marinesco-Sjogren syndrome	DISKEU0B	Strong	Biomarker	[6]
Polycystic kidney disease	DISWS3UY	Strong	Genetic Variation	[7]
Retinitis pigmentosa 80	DISVZZ56	Strong	Autosomal recessive	[5]
Short rib dysplasia	DISRBNBF	Strong	Biomarker	[8]
C syndrome	DISMHGXP	moderate	Genetic Variation	[9]
Nephronophthisis	DISXU4HY	moderate	Genetic Variation	[10]
Jeune syndrome	DISLC357	Supportive	Autosomal recessive	[2]
Leber congenital amaurosis	DISMGH8F	Supportive	Autosomal dominant	[5]
Retinitis pigmentosa	DISCGPY8	Supportive	Autosomal dominant	[5]
Infertility	DISAMOWP	Limited	CausalMutation	[11]
Meckel syndrome, type 1	DIS4YWZU	Limited	Biomarker	[12]
Nephropathy	DISXWP4P	Limited	Genetic Variation	[10]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Intraflagellar transport protein 140 homolog (IFT140).	[13]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Intraflagellar transport protein 140 homolog (IFT140).	[16]
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the methylation of Intraflagellar transport protein 140 homolog (IFT140).	[17]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Intraflagellar transport protein 140 homolog (IFT140).	[20]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Intraflagellar transport protein 140 homolog (IFT140).	[17]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Intraflagellar transport protein 140 homolog (IFT140).	[14]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Intraflagellar transport protein 140 homolog (IFT140).	[15]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Intraflagellar transport protein 140 homolog (IFT140).	[18]
GSK2110183	DMZHB37	Phase 2	GSK2110183 increases the expression of Intraflagellar transport protein 140 homolog (IFT140).	[19]

References

• [1] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [2] Mainzer-Saldino syndrome is a ciliopathy caused by IFT140 mutations. Am J Hum Genet. 2012 May 4;90(5):864-70. doi: 10.1016/j.ajhg.2012.03.006. Epub 2012 Apr 12.
• [3] Novel IFT140 variants cause spermatogenic dysfunction in humans.Mol Genet Genomic Med. 2019 Sep;7(9):e920. doi: 10.1002/mgg3.920. Epub 2019 Aug 8.
• [4] Nonsyndromic Retinal Dystrophy due to Bi-Allelic Mutations in the Ciliary Transport Gene IFT140.Invest Ophthalmol Vis Sci. 2016 Mar;57(3):1053-62. doi: 10.1167/iovs.15-17976.
• [5] Mutations in human IFT140 cause non-syndromic retinal degeneration. Hum Genet. 2015 Oct;134(10):1069-78. doi: 10.1007/s00439-015-1586-x. Epub 2015 Jul 28.
• [6] Combined NGS approaches identify mutations in the intraflagellar transport gene IFT140 in skeletal ciliopathies with early progressive kidney Disease.Hum Mutat. 2013 May;34(5):714-24. doi: 10.1002/humu.22294.
• [7] Essential Role of IFT140 in Promoting Dentinogenesis.J Dent Res. 2018 Apr;97(4):423-431. doi: 10.1177/0022034517741283. Epub 2017 Dec 1.
• [8] Genome-wide ENU mutagenesis in combination with high density SNP analysis and exome sequencing provides rapid identification of novel mouse models of developmental disease.PLoS One. 2013;8(3):e55429. doi: 10.1371/journal.pone.0055429. Epub 2013 Mar 1.
• [9] Compound heterozygous mutations in the IFT140 gene cause Opitz trigonocephaly C syndrome in a patient with typical features of a ciliopathy.Clin Genet. 2017 Apr;91(4):640-646. doi: 10.1111/cge.12924. Epub 2017 Feb 16.
• [10] Patient-iPSC-Derived Kidney Organoids Show Functional Validation of a Ciliopathic Renal Phenotype and Reveal Underlying Pathogenetic Mechanisms.Am J Hum Genet. 2018 May 3;102(5):816-831. doi: 10.1016/j.ajhg.2018.03.014. Epub 2018 Apr 26.
• [11] Impact of whole exome sequencing among Iranian patients with autosomal recessive retinitis pigmentosa.Arch Iran Med. 2015 Nov;18(11):776-85.
• [12] Intraflagellar Transport Complex A Genes Differentially Regulate Cilium Formation and Transition Zone Gating.Curr Biol. 2018 Oct 22;28(20):3279-3287.e2. doi: 10.1016/j.cub.2018.08.017. Epub 2018 Oct 4.
• [13] 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.
• [14] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [15] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [16] 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.
• [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.
• [18] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [19] Novel ATP-competitive Akt inhibitor afuresertib suppresses the proliferation of malignant pleural mesothelioma cells. Cancer Med. 2017 Nov;6(11):2646-2659. doi: 10.1002/cam4.1179. Epub 2017 Sep 27.
• [20] 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.