Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT8KPESR)

• DOT Name: Inversin (INVS)
• Synonyms: Inversion of embryo turning homolog; Nephrocystin-2
• Gene Name: INVS
• Related Disease:
  End-stage renal disease
  Epithelial ovarian cancer
  Nephronophthisis 2
  Bardet biedl syndrome
  Ciliopathy
  Joubert syndrome
  Kidney failure
  Leukemia
  Meckel syndrome, type 1
  Nephronophthisis
  Nephronophthisis 1
  Non-small-cell lung cancer
  Normal pressure hydrocephalus
  Renal fibrosis
  Retinitis pigmentosa
  Tetralogy of fallot
  Tubulointerstitial kidney disease, autosomal dominant, 2
  Alopecia
  Autosomal dominant medullary cystic kidney disease with or without hyperuricemia
  Senior-Loken syndrome
  Chronic renal failure
  Acute myelogenous leukaemia
  Advanced cancer
  Lung cancer
  Lung carcinoma
  Nephropathy
• UniProt ID: INVS_HUMAN
• Pfam ID: PF00023 ; PF12796 ; PF00612
• Sequence:
  MNKSENLLFAGSSLASQVHAAAVNGDKGALQRLIVGNSALKDKEDQFGRTPLMYCVLADR
  LDCADALLKAGADVNKTDHSQRTALHLAAQKGNYRFMKLLLTRRANWMQKDLEEMTPLHL
  TTRHRSPKCLALLLKFMAPGEVDTQDKNKQTALHWSAYYNNPEHVKLLIKHDSNIGIPDV
  EGKIPLHWAANHKDPSAVHTVRCILDAAPTESLLNWQDYEGRTPLHFAVADGNVTVVDVL
  TSYESCNITSYDNLFRTPLHWAALLGHAQIVHLLLERNKSGTIPSDSQGATPLHYAAQSN
  FAETVKVFLKHPSVKDDSDLEGRTSFMWAAGKGSDDVLRTMLSLKSDIDINMADKYGGTA
  LHAAALSGHVSTVKLLLENNAQVDATDVMKHTPLFRACEMGHKDVIQTLIKGGARVDLVD
  QDGHSLLHWAALGGNADVCQILIENKINPNVQDYAGRTPLQCAAYGGYINCMAVLMENNA
  DPNIQDKEGRTALHWSCNNGYLDAIKLLLDFAAFPNQMENNEERYTPLDYALLGERHEVI
  QFMLEHGALSIAAIQDIAAFKIQAVYKGYKVRKAFRDRKNLLMKHEQLRKDAAAKKREEE
  NKRKEAEQQKGRRSPDSCRPQALPCLPSTQDVPSRQSRAPSKQPPAGNVAQGPEPRDSRG
  SPGGSLGGALQKEQHVSSDLQGTNSRRPNETAREHSKGQSACVHFRPNEGSDGSRHPGVP
  SVEKSRGETAGDERCAKGKGFVKQPSCIRVAGPDEKGEDSRRAAASLPPHDSHWKPSRRH
  DTEPKAKCAPQKRRTQELRGGRCSPAGSSRPGSARGEAVHAGQNPPHHRTPRNKVTQAKL
  TGGLYSHLPQSTEELRSGARRLETSTLSEDFQVSKETDPAPGPLSGQSVNIDLLPVELRL
  QIIQRERRRKELFRKKNKAAAVIQRAWRSYQLRKHLSHLRHMKQLGAGDVDRWRQESTAL
  LLQVWRKELELKFPQTTAVSKAPKSPSKGTSGTKSTKHSVLKQIYGCSHEGKIHHPTRSV
  KASSVLRLNSVSNLQCIHLLENSGRSKNFSYNLQSATQPKNKTKP
• Function: Required for normal renal development and establishment of left-right axis. Probably acts as a molecular switch between different Wnt signaling pathways. Inhibits the canonical Wnt pathway by targeting cytoplasmic disheveled (DVL1) for degradation by the ubiquitin-proteasome. This suggests that it is required in renal development to oppose the repression of terminal differentiation of tubular epithelial cells by Wnt signaling. Involved in the organization of apical junctions in kidney cells together with NPHP1, NPHP4 and RPGRIP1L/NPHP8. Does not seem to be strictly required for ciliogenesis.
• Tissue Specificity: Widely expressed. Strongly expressed in the primary cilia of renal tubular cells.
• KEGG Pathway: Wnt sig.ling pathway (hsa04310)

Molecular Interaction Atlas (MIA) of This DOT

26 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
End-stage renal disease	DISXA7GG	Definitive	Genetic Variation	[1]
Epithelial ovarian cancer	DIS56MH2	Definitive	Biomarker	[2]
Nephronophthisis 2	DIS5Y5KV	Definitive	Autosomal recessive	[3]
Bardet biedl syndrome	DISTBNZW	Strong	Genetic Variation	[4]
Ciliopathy	DIS10G4I	Strong	Biomarker	[5]
Joubert syndrome	DIS7P5CO	Strong	Genetic Variation	[4]
Kidney failure	DISOVQ9P	Strong	Genetic Variation	[6]
Leukemia	DISNAKFL	Strong	Biomarker	[7]
Meckel syndrome, type 1	DIS4YWZU	Strong	Genetic Variation	[4]
Nephronophthisis	DISXU4HY	Strong	Biomarker	[8]
Nephronophthisis 1	DIS7QNQ3	Strong	Genetic Variation	[9]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[10]
Normal pressure hydrocephalus	DISOEFO9	Strong	Genetic Variation	[11]
Renal fibrosis	DISMHI3I	Strong	Biomarker	[12]
Retinitis pigmentosa	DISCGPY8	Strong	Genetic Variation	[6]
Tetralogy of fallot	DISMHFNW	Strong	Biomarker	[13]
Tubulointerstitial kidney disease, autosomal dominant, 2	DISRRBM2	Strong	Genetic Variation	[14]
Alopecia	DIS37HU4	moderate	Biomarker	[15]
Autosomal dominant medullary cystic kidney disease with or without hyperuricemia	DIS3PLLZ	moderate	Genetic Variation	[16]
Senior-Loken syndrome	DISGBSGP	Supportive	Autosomal recessive	[6]
Chronic renal failure	DISGG7K6	Disputed	Genetic Variation	[1]
Acute myelogenous leukaemia	DISCSPTN	Limited	Biomarker	[17]
Advanced cancer	DISAT1Z9	Limited	Biomarker	[18]
Lung cancer	DISCM4YA	Limited	Biomarker	[18]
Lung carcinoma	DISTR26C	Limited	Biomarker	[18]
Nephropathy	DISXWP4P	Limited	Biomarker	[18]

1 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 Inversin (INVS).	[19]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Inversin (INVS).	[20]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Inversin (INVS).	[21]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Inversin (INVS).	[22]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Inversin (INVS).	[23]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Inversin (INVS).	[24]
Glyphosate	DM0AFY7	Investigative	Glyphosate decreases the expression of Inversin (INVS).	[25]

References

• [1] Mutations of NPHP2 and NPHP3 in infantile nephronophthisis.Kidney Int. 2009 Apr;75(8):839-47. doi: 10.1038/ki.2008.662. Epub 2009 Jan 28.
• [2] Common Genetic Variation In Cellular Transport Genes and Epithelial Ovarian Cancer (EOC) Risk.PLoS One. 2015 Jun 19;10(6):e0128106. doi: 10.1371/journal.pone.0128106. eCollection 2015.
• [3] 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.
• [4] Active transport and diffusion barriers restrict Joubert Syndrome-associated ARL13B/ARL-13 to an Inv-like ciliary membrane subdomain.PLoS Genet. 2013;9(12):e1003977. doi: 10.1371/journal.pgen.1003977. Epub 2013 Dec 5.
• [5] Congenital Heart Defects and Ciliopathies Associated With Renal Phenotypes.Front Pediatr. 2018 Jun 15;6:175. doi: 10.3389/fped.2018.00175. eCollection 2018.
• [6] Retinitis pigmentosa and renal failure in a patient with mutations in INVS. Nephrol Dial Transplant. 2006 Jul;21(7):1989-91. doi: 10.1093/ndt/gfl088. Epub 2006 Mar 7.
• [7] INV(12) (p13q11) and dicentric chromosomes in a secondary leukaemia with basophilia.Haematologica. 1990 Sep-Oct;75(5):473-6.
• [8] Tubular cell loss in early inv/nphp2 mutant kidneys represents a possible homeostatic mechanism in cortical tubular formation.PLoS One. 2018 Jun 11;13(6):e0198580. doi: 10.1371/journal.pone.0198580. eCollection 2018.
• [9] A homozygous mutation in INVS causing juvenile nephronophthisis with abnormal reactivity of the Wnt/beta-catenin pathway.Nephrol Dial Transplant. 2010 Dec;25(12):4097-102. doi: 10.1093/ndt/gfq519. Epub 2010 Aug 26.
• [10] Role of transcription factor FOXA1 in nonsmall cell lung cancer.Mol Med Rep. 2018 Jan;17(1):509-521. doi: 10.3892/mmr.2017.7885. Epub 2017 Oct 26.
• [11] Nephronophthisis.Pediatr Nephrol. 2009 Dec;24(12):2333-44. doi: 10.1007/s00467-008-0840-z. Epub 2008 Jul 8.
• [12] Inhibition of the p38 MAPK pathway ameliorates renal fibrosis in an NPHP2 mouse model.Nephrol Dial Transplant. 2012 Apr;27(4):1351-8. doi: 10.1093/ndt/gfr550. Epub 2011 Nov 9.
• [13] Situs variation and cardiovascular anomalies in the transgenic mouse insertional mutation, inv.Teratology. 1998 Jun;57(6):302-9. doi: 10.1002/(SICI)1096-9926(199806)57:6<302::AID-TERA3>3.0.CO;2-Y.
• [14] New insights: nephronophthisis-medullary cystic kidney disease.Pediatr Nephrol. 2001 Feb;16(2):168-76. doi: 10.1007/s004670000518.
• [15] Cathepsin B as a potential cystatin M/E target in the mouse hair follicle.FASEB J. 2017 Oct;31(10):4286-4294. doi: 10.1096/fj.201700267R. Epub 2017 Jun 8.
• [16] Autosomal-dominant medullary cystic kidney disease type 1: clinical and molecular findings in six large Cypriot families.Kidney Int. 2002 Oct;62(4):1385-94. doi: 10.1111/j.1523-1755.2002.kid581.x.
• [17] Quantification of CBFbeta/MYH11 fusion transcript by real time RT-PCR in patients with INV(16) acute myeloid leukemia.Leukemia. 2001 Jul;15(7):1072-80. doi: 10.1038/sj.leu.2402159.
• [18] Inversin correlates with the malignant phenotype of non-small cell lung cancer and promotes the invasiveness of lung cancer cells.Tumour Biol. 2017 Jun;39(6):1010428317691177. doi: 10.1177/1010428317691177.
• [19] 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.
• [20] 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.
• [21] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [22] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [23] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [24] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [25] Glyphosate-based herbicides at low doses affect canonical pathways in estrogen positive and negative breast cancer cell lines. PLoS One. 2019 Jul 11;14(7):e0219610. doi: 10.1371/journal.pone.0219610. eCollection 2019.