Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT8U8ELA)

• DOT Name: Nephrocystin-3 (NPHP3)
• Gene Name: NPHP3
• Related Disease:
  End-stage renal disease
  Nephronophthisis
  Nephronophthisis 3
  Autosomal recessive polycystic kidney disease
  Ciliopathy
  Congenital anomaly of kidney and urinary tract
  Congenital heart disease
  Congenital nervous system disorder
  Normal pressure hydrocephalus
  Retinitis pigmentosa
  Tubulointerstitial kidney disease, autosomal dominant, 2
  Obstructive jaundice
  Polycystic kidney disease
  Retinopathy
  Sjogren-Larsson syndrome
  Late-onset nephronophthisis
  Nephronophthisis 2
  NPHP3-related Meckel-like syndrome
  Renal-hepatic-pancreatic dysplasia
  Senior-Loken syndrome
  Chronic renal failure
• UniProt ID: NPHP3_HUMAN
• PDB ID: 5L7K
• Pfam ID: PF13424 ; PF13176
• Sequence:
  MGTASSLVSPAGGEVIEDTYGAGGGEACEIPVEVKPKARLLRNSFRRGAGAAAGAGPGSL
  PRGVGAGGLLGASFKSTGSSVPELEYAAAEYERLRKEYEIFRVSKNQELLSMGRREAKLD
  TENKRLRAELQALQKTYQKILREKESALEAKYQAMERAATFEHDRDKVKRQFKIFRETKE
  NEIQDLLRAKRELESKLQRLQAQGIQVFDPGESDSDDNCTDVTAAGTQCEYWTGGALGSE
  PSIGSMIQLQQSFRGPEFAHSSIDVEGPFANVNRDDWDIAVASLLQVTPLFSHSLWSNTV
  RCYLIYTDETQPEMDLFLKDYSPKLKRMCETMGYFFHAVYFPIDVENQYLTVRKWEIEKS
  SLVILFIHLTLPSLLLEDCEEAFLKNPEGKPRLIFHRLEDGKVSSDSVQQLIDQVSNLNK
  TSKAKIIDHSGDPAEGVYKTYICVEKIIKQDILGFENTDLETKDLGSEDSIPEEDDFGDV
  LWDIHDEQEQMETFQQASNSAHELGFEKYYQRLNDLVAAPAPIPPLLVSGGPGSGKSLLL
  SKWIQLQQKNSPNTLILSHFVGRPMSTSSESSLIIKRLTLKLMQHSWSVSALTLDPAKLL
  EEFPRWLEKLSARHQGSIIIVIDSIDQVQQVEKHMKWLIDPLPVNVRVIVSVNVETCPPA
  WRLWPTLHLDPLSPKDAKSIIIAECHSVDIKLSKEQEKKLERHCRSATTCNALYVTLFGK
  MIARAGRAGNLDKILHQCFQCQDTLSLYRLVLHSIRESMANDVDKELMKQILCLVNVSHN
  GVSESELMELYPEMSWTFLTSLIHSLYKMCLLTYGCGLLRFQHLQAWETVRLEYLEGPTV
  TSSYRQKLINYFTLQLSQDRVTWRSADELPWLFQQQGSKQKLHDCLLNLFVSQNLYKRGH
  FAELLSYWQFVGKDKSAMATEYFDSLKQYEKNCEGEDNMSCLADLYETLGRFLKDLGLLS
  QAIVPLQRSLEIRETALDPDHPRVAQSLHQLASVYVQWKKFGNAEQLYKQALEISENAYG
  ADHPYTARELEALATLYQKQNKYEQAEHFRKKSFKIHQKAIKKKGNLYGFALLRRRALQL
  EELTLGKDTPDNARTLNELGVLYYLQNNLETADQFLKRSLEMRERVLGPDHPDCAQSLNN
  LAALCNEKKQYDKAEELYERALDIRRRALAPDHPSLAYTVKHLAILYKKMGKLDKAVPLY
  ELAVEIRQKSFGPKHPSVATALVNLAVLYSQMKKHVEALPLYERALKIYEDSLGRMHPRV
  GETLKNLAVLSYEGGDFEKAAELYKRAMEIKEAETSLLGGKAPSRHSSSGDTFSLKTAHS
  PNVFLQQGQR
• Function: Required for normal ciliary development and function. Inhibits disheveled-1-induced canonical Wnt-signaling activity and may also play a role in the control of non-canonical Wnt signaling which regulates planar cell polarity. Probably acts as a molecular switch between different Wnt signaling pathways. Required for proper convergent extension cell movements.
• Tissue Specificity: Widely expressed at low level. Expressed in heart, placenta, liver, skeletal muscle, kidney and pancreas. Expressed at very low level in brain and lung.
• Reactome Pathway: Trafficking of myristoylated proteins to the cilium (R-HSA-5624138)

Molecular Interaction Atlas (MIA) of This DOT

21 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]
Nephronophthisis	DISXU4HY	Definitive	Autosomal recessive	[2]
Nephronophthisis 3	DIS4CC6R	Definitive	Autosomal recessive	[3]
Autosomal recessive polycystic kidney disease	DISPUS40	Strong	Biomarker	[4]
Ciliopathy	DIS10G4I	Strong	Genetic Variation	[5]
Congenital anomaly of kidney and urinary tract	DIS84IVH	Strong	Genetic Variation	[6]
Congenital heart disease	DISQBA23	Strong	Genetic Variation	[7]
Congenital nervous system disorder	DIS2BIP8	Strong	Genetic Variation	[8]
Normal pressure hydrocephalus	DISOEFO9	Strong	Genetic Variation	[9]
Retinitis pigmentosa	DISCGPY8	Strong	Genetic Variation	[6]
Tubulointerstitial kidney disease, autosomal dominant, 2	DISRRBM2	Strong	Genetic Variation	[10]
Obstructive jaundice	DIS2FDOT	moderate	Genetic Variation	[11]
Polycystic kidney disease	DISWS3UY	moderate	Genetic Variation	[12]
Retinopathy	DISB4B0F	moderate	Biomarker	[13]
Sjogren-Larsson syndrome	DISP943Y	moderate	Genetic Variation	[13]
Late-onset nephronophthisis	DIS8G9LN	Supportive	Autosomal recessive	[14]
Nephronophthisis 2	DIS5Y5KV	Supportive	Autosomal recessive	[7]
NPHP3-related Meckel-like syndrome	DIS2QQIV	Supportive	Autosomal recessive	[6]
Renal-hepatic-pancreatic dysplasia	DIS3L6GZ	Supportive	Autosomal recessive	[15]
Senior-Loken syndrome	DISGBSGP	Supportive	Autosomal recessive	[16]
Chronic renal failure	DISGG7K6	Disputed	Genetic Variation	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of Nephrocystin-3 (NPHP3).	[17]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Nephrocystin-3 (NPHP3).	[18]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Nephrocystin-3 (NPHP3).	[19]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Nephrocystin-3 (NPHP3).	[20]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Nephrocystin-3 (NPHP3).	[21]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Nephrocystin-3 (NPHP3).	[22]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Nephrocystin-3 (NPHP3).	[23]
Coumestrol	DM40TBU	Investigative	Coumestrol decreases the expression of Nephrocystin-3 (NPHP3).	[24]

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] 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] Lethal cystic kidney disease in Amish neonates associated with homozygous nonsense mutation of NPHP3. Am J Kidney Dis. 2009 May;53(5):790-5. doi: 10.1053/j.ajkd.2008.12.026. Epub 2009 Mar 20.
• [4] Altered expression pattern of polycystin-2 in acute and chronic renal tubular diseases.J Am Soc Nephrol. 2002 Jul;13(7):1855-64. doi: 10.1097/01.asn.0000018402.33620.c7.
• [5] Homozygous mutation in the NPHP3 gene causing foetal nephronophthisis.Nephrology (Carlton). 2017 Oct;22(10):818-820. doi: 10.1111/nep.13097.
• [6] Loss of nephrocystin-3 function can cause embryonic lethality, Meckel-Gruber-like syndrome, situs inversus, and renal-hepatic-pancreatic dysplasia. Am J Hum Genet. 2008 Apr;82(4):959-70. doi: 10.1016/j.ajhg.2008.02.017. Epub 2008 Mar 27.
• [7] High mutation rate of NPHP3 in 18 Chinese infantile nephronophthisis patients. Nephrology (Carlton). 2016 Mar;21(3):209-16. doi: 10.1111/nep.12563.
• [8] Renal-hepatic-pancreatic dysplasia: a sibship with skeletal and central nervous system anomalies and NPHP3 mutation.Am J Med Genet A. 2013 Jul;161A(7):1743-9. doi: 10.1002/ajmg.a.35958. Epub 2013 May 17.
• [9] Molecular genetics of nephronophthisis and medullary cystic kidney disease.J Am Soc Nephrol. 2000 Sep;11(9):1753-1761. doi: 10.1681/ASN.V1191753.
• [10] New insights: nephronophthisis-medullary cystic kidney disease.Pediatr Nephrol. 2001 Feb;16(2):168-76. doi: 10.1007/s004670000518.
• [11] Isosorbide dinitrate in nephronophthisis treatment.Am J Med Genet A. 2018 Apr;176(4):1023-1026. doi: 10.1002/ajmg.a.38650.
• [12] Nephrocystin-3 is required for ciliary function in zebrafish embryos.Am J Physiol Renal Physiol. 2010 Jul;299(1):F55-62. doi: 10.1152/ajprenal.00043.2010. Epub 2010 May 12.
• [13] Candidate gene analysis of KIAA0678 encoding a DnaJ-like protein for adolescent nephronophthisis and Senior-Lken syndrome type 3.Cytogenet Genome Res. 2002;97(3-4):163-6. doi: 10.1159/000066617.
• [14] 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.
• [15] Identification of a gene for renal-hepatic-pancreatic dysplasia by microarray-based homozygosity mapping. J Mol Diagn. 2010 Jan;12(1):125-31. doi: 10.2353/jmoldx.2010.090033. Epub 2009 Dec 10.
• [16] 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.
• [17] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [18] 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.
• [19] 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.
• [20] 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.
• [21] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [22] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [23] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [24] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.