Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTBNOA7U)

• DOT Name: Nephrocystin-4 (NPHP4)
• Synonyms: Nephroretinin
• Gene Name: NPHP4
• Related Disease:
  Nephronophthisis 4
  Senior-Loken syndrome 4
  Ciliopathy
  Focal segmental glomerulosclerosis
  Male infertility
  Nephronophthisis
  Nephronophthisis 2
  Nephropathy
  Normal pressure hydrocephalus
  Retinitis pigmentosa
  Nephronophthisis 3
  Nephronophthisis 1
  Senior-Loken syndrome
  Joubert syndrome
  Joubert syndrome with oculorenal defect
• UniProt ID: NPHP4_HUMAN
• Sequence:
  MNDWHRIFTQNVLVPPHPQRARQPWKESTAFQCVLKWLDGPVIRQGVLEVLSEVECHLRV
  SFFDVTYRHFFGRTWKTTVKPTKRPPSRIVFNEPLYFHTSLNHPHIVAVVEVVAEGKKRD
  GSLQTLSCGFGILRIFSNQPDSPISASQDKRLRLYHGTPRALLHPLLQDPAEQNRHMTLI
  ENCSLQYTLKPHPALEPAFHLLPENLLVSGLQQIPGLLPAHGESGDALRKPRLQKPITGH
  LDDLFFTLYPSLEKFEEELLELHVQDHFQEGCGPLDGGALEILERRLRVGVHNGLGFVQR
  PQVVVLVPEMDVALTRSASFSRKVVSSSKTSSGSQALVLRSRLRLPEMVGHPAFAVIFQL
  EYVFSSPAGVDGNAASVTSLSNLACMHMVRWAVWNPLLEADSGRVTLPLQGGIQPNPSHC
  LVYKVPSASMSSEEVKQVESGTLRFQFSLGSEEHLDAPTEPVSGPKVERRPSRKPPTSPS
  SPPAPVPRVLAAPQNSPVGPGLSISQLAASPRSPTQHCLARPTSQLPHGSQASPAQAQEF
  PLEAGISHLEADLSQTSLVLETSIAEQLQELPFTPLHAPIVVGTQTRSSAGQPSRASMVL
  LQSSGFPEILDANKQPAEAVSATEPVTFNPQKEESDCLQSNEMVLQFLAFSRVAQDCRGT
  SWPKTVYFTFQFYRFPPATTPRLQLVQLDEAGQPSSGALTHILVPVSRDGTFDAGSPGFQ
  LRYMVGPGFLKPGERRCFARYLAVQTLQIDVWDGDSLLLIGSAAVQMKHLLRQGRPAVQA
  SHELEVVATEYEQDNMVVSGDMLGFGRVKPIGVHSVVKGRLHLTLANVGHPCEQKVRGCS
  TLPPSRSRVISNDGASRFSGGSLLTTGSSRRKHVVQAQKLADVDSELAAMLLTHARQGKG
  PQDVSRESDATRRRKLERMRSVRLQEAGGDLGRRGTSVLAQQSVRTQHLRDLQVIAAYRE
  RTKAESIASLLSLAITTEHTLHATLGVAEFFEFVLKNPHNTQHTVTVEIDNPELSVIVDS
  QEWRDFKGAAGLHTPVEEDMFHLRGSLAPQLYLRPHETAHVPFKFQSFSAGQLAMVQASP
  GLSNEKGMDAVSPWKSSAVPTKHAKVLFRASGGKPIAVLCLTVELQPHVVDQVFRFYHPE
  LSFLKKAIRLPPWHTFPGAPVGMLGEDPPVHVRCSDPNVICETQNVGPGEPRDIFLKVAS
  GPSPEIKDFFVIIYSDRWLATPTQTWQVYLHSLQRVDVSCVAGQLTRLSLVLRGTQTVRK
  VRAFTSHPQELKTDPKGVFVLPPRGVQDLHVGVRPLRAGSRFVHLNLVDVDCHQLVASWL
  VCLCCRQPLISKAFEIMLAAGEGKGVNKRITYTNPYPSRRTFHLHSDHPELLRFREDSFQ
  VGGGETYTIGLQFAPSQRVGEEEILIYINDHEDKNEEAFCVKVIYQ
• Function: Involved in the organization of apical junctions; the function is proposed to implicate a NPHP1-4-8 module. Does not seem to be strictly required for ciliogenesis. Required for building functional cilia. Involved in the organization of the subapical actin network in multiciliated epithelial cells. Seems to recruit INT to basal bodies of motile cilia which subsequently interacts with actin-modifying proteins such as DAAM1. In cooperation with INVS may down-regulate the canonical Wnt pathway and promote the Wnt-PCP pathway by regulating expression and subcellular location of disheveled proteins. Stabilizes protein levels of JADE1 and promotes its translocation to the nucleus leading to cooperative inhibition of canonical Wnt signaling. Acts as a negative regulator of the hippo pathway by association with LATS1 and modifying LATS1-dependent phosphorylation and localization of WWTR1/TAZ.
• Tissue Specificity: Expressed in kidney, skeletal muscle, heart and liver, and to a lesser extent in brain and lung.
• Reactome Pathway:
  Anchoring of the basal body to the plasma membrane (R-HSA-5620912)
  Signaling by Hippo (R-HSA-2028269)

Molecular Interaction Atlas (MIA) of This DOT

15 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Nephronophthisis 4	DISEMDTR	Definitive	Autosomal recessive	[1]
Senior-Loken syndrome 4	DISRY70P	Definitive	Autosomal recessive	[2]
Ciliopathy	DIS10G4I	Strong	Biomarker	[3]
Focal segmental glomerulosclerosis	DISJNHH0	Strong	Genetic Variation	[4]
Male infertility	DISY3YZZ	Strong	Biomarker	[5]
Nephronophthisis	DISXU4HY	Strong	Biomarker	[6]
Nephronophthisis 2	DIS5Y5KV	Strong	Genetic Variation	[7]
Nephropathy	DISXWP4P	Strong	Genetic Variation	[8]
Normal pressure hydrocephalus	DISOEFO9	Strong	Genetic Variation	[9]
Retinitis pigmentosa	DISCGPY8	Strong	Genetic Variation	[10]
Nephronophthisis 3	DIS4CC6R	moderate	Biomarker	[11]
Nephronophthisis 1	DIS7QNQ3	Supportive	Autosomal recessive	[12]
Senior-Loken syndrome	DISGBSGP	Supportive	Autosomal recessive	[13]
Joubert syndrome	DIS7P5CO	Limited	Genetic Variation	[5]
Joubert syndrome with oculorenal defect	DISU0IPO	Limited	Genetic Variation	[5]

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 Nephrocystin-4 (NPHP4).	[14]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Nephrocystin-4 (NPHP4).	[15]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Nephrocystin-4 (NPHP4).	[18]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Nephrocystin-4 (NPHP4).	[16]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Nephrocystin-4 (NPHP4).	[17]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Nephrocystin-4 (NPHP4).	[19]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Nephrocystin-4 (NPHP4).	[20]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of Nephrocystin-4 (NPHP4).	[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] Flexible and scalable diagnostic filtering of genomic variants using G2P with Ensembl VEP. Nat Commun. 2019 May 30;10(1):2373. doi: 10.1038/s41467-019-10016-3.
• [3] The ciliary gene RPGRIP1L is mutated in cerebello-oculo-renal syndrome (Joubert syndrome type B) and Meckel syndrome. Nat Genet. 2007 Jul;39(7):875-81. doi: 10.1038/ng2039. Epub 2007 Jun 10.
• [4] Novel mutations in NPHP4 in a consanguineous family with histological findings of focal segmental glomerulosclerosis.Am J Kidney Dis. 2007 Nov;50(5):855-64. doi: 10.1053/j.ajkd.2007.08.009.
• [5] NPHP4 mutation is linked to cerebello-oculo-renal syndrome and male infertility.Clin Genet. 2014 Apr;85(4):371-5. doi: 10.1111/cge.12160. Epub 2013 Apr 26.
• [6] Adult-Diagnosed Nonsyndromic Nephronophthisis in Australian Families Caused by Biallelic NPHP4 Variants.Am J Kidney Dis. 2020 Aug;76(2):282-287. doi: 10.1053/j.ajkd.2019.08.031. Epub 2019 Dec 4.
• [7] Mutations in INVS encoding inversin cause nephronophthisis type 2, linking renal cystic disease to the function of primary cilia and left-right axis determination. Nat Genet. 2003 Aug;34(4):413-20. doi: 10.1038/ng1217.
• [8] NPHP4, a cilia-associated protein, negatively regulates the Hippo pathway.J Cell Biol. 2011 May 16;193(4):633-42. doi: 10.1083/jcb.201009069. Epub 2011 May 9.
• [9] Mutational analysis of the NPHP4 gene in 250 patients with nephronophthisis.Hum Mutat. 2005 Apr;25(4):411. doi: 10.1002/humu.9326.
• [10] Interaction of nephrocystin-4 and RPGRIP1 is disrupted by nephronophthisis or Leber congenital amaurosis-associated mutations.Proc Natl Acad Sci U S A. 2005 Dec 20;102(51):18520-5. doi: 10.1073/pnas.0505774102. Epub 2005 Dec 9.
• [11] Analysis of the NPHP genes in two Japanese patients with suspected sporadic juvenile or adolescent nephronophthisis.Clin Nephrol. 2006 May;65(5):364-9. doi: 10.5414/cnp65364.
• [12] Clinical Practice Guidelines for Rare Diseases: The Orphanet Database. PLoS One. 2017 Jan 18;12(1):e0170365. doi: 10.1371/journal.pone.0170365. eCollection 2017.
• [13] Senior-L?ken syndrome: a syndromic form of retinal dystrophy associated with nephronophthisis. Vision Res. 2012 Dec 15;75:88-97. doi: 10.1016/j.visres.2012.07.003. Epub 2012 Jul 20.
• [14] 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.
• [15] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [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] Effect of aflatoxin B(1), benzo[a]pyrene, and methapyrilene on transcriptomic and epigenetic alterations in human liver HepaRG cells. Food Chem Toxicol. 2018 Nov;121:214-223. doi: 10.1016/j.fct.2018.08.034. Epub 2018 Aug 26.
• [18] 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.
• [19] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [20] 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.