Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTSK3OAD)

• DOT Name: Intraflagellar transport protein 122 homolog (IFT122)
• Synonyms: WD repeat-containing protein 10; WD repeat-containing protein 140
• Gene Name: IFT122
• Related Disease:
  Ciliopathy
  Cranioectodermal dysplasia 1
  Beemer-Langer syndrome
  Camurati-Engelmann disease
  Coeliac disease
  Communicating hydrocephalus
  Congenital hydrocephalus
  Craniosynostosis
  Craniosynostosis 4
  Hepatitis C virus infection
  Hereditary spastic paraplegia
  Hereditary spastic paraplegia 4
  Hereditary spastic paraplegia 45
  Hydrocephalus
  Inflammatory bowel disease
  Neoplasm
  Nephropathy
  Pelizeaus-Merzbacher spectrum disorder
  Primary ciliary dyskinesia
  Scleroderma
  Systemic sclerosis
  Tarsal-carpal coalition syndrome
  Trigonocephaly
  Tuberculosis
  TWIST1-related craniosynostosis
  Cranioectodermal dysplasia
  Anxiety
  Anxiety disorder
• UniProt ID: IF122_HUMAN
• PDB ID: 8BBE; 8BBF; 8BBG; 8FGW; 8FH3
• Pfam ID: PF00400
• Sequence:
  MRAVLTWRDKAEHCINDIAFKPDGTQLILAAGSRLLVYDTSDGTLLQPLKGHKDTVYCVA
  YAKDGKRFASGSADKSVIIWTSKLEGILKYTHNDAIQCVSYNPITHQLASCSSSDFGLWS
  PEQKSVSKHKSSSKIICCSWTNDGQYLALGMFNGIISIRNKNGEEKVKIERPGGSLSPIW
  SICWNPSSRWESFWMNRENEDAEDVIVNRYIQEIPSTLKSAVYSSQGSEAEEEEPEEEDD
  SPRDDNLEERNDILAVADWGQKVSFYQLSGKQIGKDRALNFDPCCISYFTKGEYILLGGS
  DKQVSLFTKDGVRLGTVGEQNSWVWTCQAKPDSNYVVVGCQDGTISFYQLIFSTVHGLYK
  DRYAYRDSMTDVIVQHLITEQKVRIKCKELVKKIAIYRNRLAIQLPEKILIYELYSEDLS
  DMHYRVKEKIIKKFECNLLVVCANHIILCQEKRLQCLSFSGVKEREWQMESLIRYIKVIG
  GPPGREGLLVGLKNGQILKIFVDNLFAIVLLKQATAVRCLDMSASRKKLAVVDENDTCLV
  YDIDTKELLFQEPNANSVAWNTQCEDMLCFSGGGYLNIKASTFPVHRQKLQGFVVGYNGS
  KIFCLHVFSISAVEVPQSAPMYQYLDRKLFKEAYQIACLGVTDTDWRELAMEALEGLDFE
  TAKKAFIRVQDLRYLELISSIEERKKRGETNNDLFLADVFSYQGKFHEAAKLYKRSGHEN
  LALEMYTDLCMFEYAKDFLGSGDPKETKMLITKQADWARNIKEPKAAVEMYISAGEHVKA
  IEICGDHGWVDMLIDIARKLDKAEREPLLLCATYLKKLDSPGYAAETYLKMGDLKSLVQL
  HVETQRWDEAFALGEKHPEFKDDIYMPYAQWLAENDRFEEAQKAFHKAGRQREAVQVLEQ
  LTNNAVAESRFNDAAYYYWMLSMQCLDIAQDPAQKDTMLGKFYHFQRLAELYHGYHAIHR
  HTEDPFSVHRPETLFNISRFLLHSLPKDTPSGISKVKILFTLAKQSKALGAYRLARHAYD
  KLRGLYIPARFQKSIELGTLTIRAKPFHDSEELVPLCYRCSTNNPLLNNLGNVCINCRQP
  FIFSASSYDVLHLVEFYLEEGITDEEAISLIDLEVLRPKRDDRQLEIANNSSQILRLVET
  KDSIGDEDPFTAKLSFEQGGSEFVPVVVSRLVLRSMSRRDVLIKRWPPPLRWQYFRSLLP
  DASITMCPSCFQMFHSEDYELLVLQHGCCPYCRRCKDDPGP
• Function: As a 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), it is required in ciliogenesis and ciliary protein trafficking. Involved in cilia formation during neuronal patterning. Acts as a negative regulator of Shh signaling. Required to recruit TULP3 to primary cilia.
• Tissue Specificity: Expressed in many tissues. Predominant expression in testis and pituitary.
• Reactome Pathway:
  Intraflagellar transport (R-HSA-5620924)
  Hedgehog 'off' state (R-HSA-5610787)

Molecular Interaction Atlas (MIA) of This DOT

28 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Ciliopathy	DIS10G4I	Definitive	Genetic Variation	[1]
Cranioectodermal dysplasia 1	DISN81L4	Definitive	Autosomal recessive	[2]
Beemer-Langer syndrome	DIS3TBQE	Strong	Genetic Variation	[3]
Camurati-Engelmann disease	DISTJPCE	Strong	Genetic Variation	[4]
Coeliac disease	DISIY60C	Strong	Altered Expression	[5]
Communicating hydrocephalus	DIS33112	Strong	Biomarker	[6]
Congenital hydrocephalus	DIS7O6UL	Strong	Biomarker	[6]
Craniosynostosis	DIS6J405	Strong	Biomarker	[6]
Craniosynostosis 4	DISZX1GK	Strong	Biomarker	[6]
Hepatitis C virus infection	DISQ0M8R	Strong	Biomarker	[7]
Hereditary spastic paraplegia	DISGZQV1	Strong	Genetic Variation	[8]
Hereditary spastic paraplegia 4	DISFUYL2	Strong	Genetic Variation	[9]
Hereditary spastic paraplegia 45	DISGQU26	Strong	Biomarker	[10]
Hydrocephalus	DISIZUF7	Strong	Biomarker	[6]
Inflammatory bowel disease	DISGN23E	Strong	Altered Expression	[5]
Neoplasm	DISZKGEW	Strong	Biomarker	[11]
Nephropathy	DISXWP4P	Strong	Biomarker	[6]
Pelizeaus-Merzbacher spectrum disorder	DIS1ODJO	Strong	Biomarker	[12]
Primary ciliary dyskinesia	DISOBC7V	Strong	Biomarker	[6]
Scleroderma	DISVQ342	Strong	Biomarker	[13]
Systemic sclerosis	DISF44L6	Strong	Biomarker	[13]
Tarsal-carpal coalition syndrome	DISY90L2	Strong	Biomarker	[10]
Trigonocephaly	DISHV6BA	Strong	Biomarker	[6]
Tuberculosis	DIS2YIMD	Strong	Biomarker	[14]
TWIST1-related craniosynostosis	DISGRP2G	Strong	Biomarker	[6]
Cranioectodermal dysplasia	DISW7Y64	Supportive	Autosomal recessive	[15]
Anxiety	DISIJDBA	Limited	Biomarker	[16]
Anxiety disorder	DISBI2BT	Limited	Biomarker	[16]

2 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 122 homolog (IFT122).	[17]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Intraflagellar transport protein 122 homolog (IFT122).	[20]

3 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 122 homolog (IFT122).	[18]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Intraflagellar transport protein 122 homolog (IFT122).	[19]
Coumestrol	DM40TBU	Investigative	Coumestrol decreases the expression of Intraflagellar transport protein 122 homolog (IFT122).	[21]

References

• [1] Clinical and molecular genetic characterization of a male patient with Sensenbrenner syndrome (cranioectodermal dysplasia) and biallelic WDR35 mutations.Birth Defects Res. 2018 Mar 1;110(4):376-381. doi: 10.1002/bdr2.1151. Epub 2017 Nov 14.
• [2] 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.
• [3] Beemer-Langer syndrome is a ciliopathy due to biallelic mutations in IFT122.Am J Med Genet A. 2017 May;173(5):1186-1189. doi: 10.1002/ajmg.a.38157. Epub 2017 Mar 28.
• [4] Ciliopathy-associated mutations of IFT122 impair ciliary protein trafficking but not ciliogenesis.Hum Mol Genet. 2018 Feb 1;27(3):516-528. doi: 10.1093/hmg/ddx421.
• [5] The association between de novo inflammatory bowel disease and celiac disease.Rev Esp Enferm Dig. 2020 Jan;112(1):7-11. doi: 10.17235/reed.2019.5535/2018.
• [6] Cranioectodermal Dysplasia, Sensenbrenner syndrome, is a ciliopathy caused by mutations in the IFT122 gene. Am J Hum Genet. 2010 Jun 11;86(6):949-56. doi: 10.1016/j.ajhg.2010.04.012. Epub 2010 May 20.
• [7] Induction of humoural and cellular immunity by immunisation with HCV particle vaccine in a non-human primate model.Gut. 2018 Feb;67(2):372-379. doi: 10.1136/gutjnl-2016-312208. Epub 2016 Oct 26.
• [8] Genetic analysis of SPG4 and SPG3A genes in a cohort of Chinese patients with hereditary spastic paraplegia.J Neurol Sci. 2014 Dec 15;347(1-2):368-71. doi: 10.1016/j.jns.2014.10.017. Epub 2014 Oct 16.
• [9] Partial SPAST and DPY30 deletions in a Japanese spastic paraplegia type 4 family.Neurogenetics. 2011 Feb;12(1):25-31. doi: 10.1007/s10048-010-0260-7. Epub 2010 Sep 22.
• [10] NT5C2 novel splicing variant expands the phenotypic spectrum of Spastic Paraplegia (SPG45): case report of a new member of thin corpus callosum SPG-Subgroup.BMC Med Genet. 2017 Mar 21;18(1):33. doi: 10.1186/s12881-017-0395-6.
• [11] Characterization of the distribution, retention, and efficacy of internal radiation of (188)Re-lipid nanocapsules in an immunocompromised human glioblastoma model.J Neurooncol. 2017 Jan;131(1):49-58. doi: 10.1007/s11060-016-2289-4. Epub 2016 Oct 25.
• [12] Genotype-phenotype correlation in inherited brain myelination defects due to proteolipid protein gene mutations. Clinical European Network on Brain Dysmyelinating Disease.Eur J Hum Genet. 2000 Nov;8(11):837-45. doi: 10.1038/sj.ejhg.5200537.
• [13] Facile fabrication of PEG-coated PLGA microspheres via SPG membrane emulsification for the treatment of scleroderma by ECM degrading enzymes.Colloids Surf B Biointerfaces. 2019 Jul 1;179:453-461. doi: 10.1016/j.colsurfb.2019.04.028. Epub 2019 Apr 14.
• [14] Structure-based virtual screening, molecular dynamics simulation and MM-PBSA toward identifying the inhibitors for two-component regulatory system protein NarL of Mycobacterium Tuberculosis.J Biomol Struct Dyn. 2020 Jul;38(11):3396-3410. doi: 10.1080/07391102.2019.1657499. Epub 2019 Aug 26.
• [15] 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.
• [16] Contribution of health motive to cannabis use among high-school students.Addict Behav. 2017 Jan;64:54-56. doi: 10.1016/j.addbeh.2016.08.011. Epub 2016 Aug 10.
• [17] 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.
• [18] 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.
• [19] 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.
• [20] 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.
• [21] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.