Details of Drug Off-Target (DOT)

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

• DOT Name: Nephrocystin-1 (NPHP1)
• Synonyms: Juvenile nephronophthisis 1 protein
• Gene Name: NPHP1
• Related Disease:
  Joubert syndrome with renal defect
  Nephronophthisis 1
  Alport syndrome
  Alzheimer disease
  Arteriosclerosis
  Chronic renal failure
  Ciliopathy
  Dandy-Walker syndrome
  End-stage renal disease
  Focal segmental glomerulosclerosis
  Johanson-Blizzard syndrome
  Nephronophthisis 2
  Ocular motor apraxia, Cogan type
  Retinal degeneration
  Age-related macular degeneration
  Nephropathy
  Normal pressure hydrocephalus
  Bardet biedl syndrome
  Senior-Loken syndrome
  Childhood kidney Wilms tumor
  Intellectual disability
  Kidney failure
  Wilms tumor
  Autoimmune polyendocrinopathy
  Familial nephrotic syndrome
  Meckel syndrome, type 1
• UniProt ID: NPHP1_HUMAN
• PDB ID: 1S1N; 6O1Q
• Pfam ID: PF00018
• Sequence:
  MLARRQRDPLQALRRRNQELKQQVDSLLSESQLKEALEPNKRQHIYQRCIQLKQAIDENK
  NALQKLSKADESAPVANYNQRKEEEHTLLDKLTQQLQGLAVTISRENITEVGAPTEEEEE
  SESEDSEDSGGEEEDAEEEEEEKEENESHKWSTGEEYIAVGDFTAQQVGDLTFKKGEILL
  VIEKKPDGWWIAKDAKGNEGLVPRTYLEPYSEEEEGQESSEEGSEEDVEAVDETADGAEV
  KQRTDPHWSAVQKAISEAGIFCLVNHVSFCYLIVLMRNRMETVEDTNGSETGFRAWNVQS
  RGRIFLVSKPVLQINTVDVLTTMGAIPAGFRPSTLSQLLEEGNQFRANYFLQPELMPSQL
  AFRDLMWDATEGTIRSRPSRISLILTLWSCKMIPLPGMSIQVLSRHVRLCLFDGNKVLSN
  IHTVRATWQPKKPKTWTFSPQVTRILPCLLDGDCFIRSNSASPDLGILFELGISYIRNST
  GERGELSCGWVFLKLFDASGVPIPAKTYELFLNGGTPYEKGIEVDPSISRRAHGSVFYQI
  MTMRRQPQLLVKLRSLNRRSRNVLSLLPETLIGNMCSIHLLIFYRQILGDVLLKDRMSLQ
  STDLISHPMLATFPMLLEQPDVMDALRSSWAGKESTLKRSEKRDKEFLKSTFLLVYHDCV
  LPLLHSTRLPPFRWAEEETETARWKVITDFLKQNQENQGALQALLSPDGVHEPFDLSEQT
  YDFLGEMRKNAV
• Function: Together with BCAR1 it may play a role in the control of epithelial cell polarity. Involved in the organization of apical junctions in kidney cells together with NPHP4 and RPGRIP1L/NPHP8. Does not seem to be strictly required for ciliogenesis. Seems to help to recruit PTK2B/PYK2 to cell matrix adhesions, thereby initiating phosphorylation of PTK2B/PYK2 and PTK2B/PYK2-dependent signaling. May play a role in the regulation of intraflagellar transport (IFT) during cilia assembly. Required for normal retina development. In connecting photoreceptor cilia influences the movement of some IFT proteins such as IFT88 and WDR19. Involved in spermatogenesis.
• Tissue Specificity: Widespread expression, with highest levels in pituitary gland, spinal cord, thyroid gland, testis, skeletal muscle, lymph node and trachea. Weakly expressed in heart, kidney and pancreas. Expressed in nasal epithelial cells (at protein level) . Expressed in the renal collecting duct (at protein level) .
• Reactome Pathway: Anchoring of the basal body to the plasma membrane (R-HSA-5620912)

Molecular Interaction Atlas (MIA) of This DOT

26 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Joubert syndrome with renal defect	DIS52E3N	Definitive	Autosomal recessive	[1]
Nephronophthisis 1	DIS7QNQ3	Definitive	Autosomal recessive	[2]
Alport syndrome	DIS25AB4	Strong	Genetic Variation	[3]
Alzheimer disease	DISF8S70	Strong	Genetic Variation	[4]
Arteriosclerosis	DISK5QGC	Strong	Genetic Variation	[5]
Chronic renal failure	DISGG7K6	Strong	Biomarker	[6]
Ciliopathy	DIS10G4I	Strong	Biomarker	[7]
Dandy-Walker syndrome	DIS4HC6W	Strong	Genetic Variation	[8]
End-stage renal disease	DISXA7GG	Strong	Biomarker	[6]
Focal segmental glomerulosclerosis	DISJNHH0	Strong	Genetic Variation	[9]
Johanson-Blizzard syndrome	DISYNPE8	Strong	Genetic Variation	[10]
Nephronophthisis 2	DIS5Y5KV	Strong	Genetic Variation	[11]
Ocular motor apraxia, Cogan type	DIS32GGL	Strong	Genetic Variation	[12]
Retinal degeneration	DISM1JHQ	Strong	Biomarker	[13]
Age-related macular degeneration	DIS0XS2C	moderate	Biomarker	[14]
Nephropathy	DISXWP4P	moderate	Genetic Variation	[15]
Normal pressure hydrocephalus	DISOEFO9	moderate	Genetic Variation	[16]
Bardet biedl syndrome	DISTBNZW	Supportive	Autosomal recessive	[7]
Senior-Loken syndrome	DISGBSGP	Supportive	Autosomal recessive	[17]
Childhood kidney Wilms tumor	DIS0NMK3	Disputed	Genetic Variation	[18]
Intellectual disability	DISMBNXP	Disputed	Genetic Variation	[19]
Kidney failure	DISOVQ9P	Disputed	Biomarker	[13]
Wilms tumor	DISB6T16	Disputed	Genetic Variation	[18]
Autoimmune polyendocrinopathy	DISOLDB2	Limited	Biomarker	[20]
Familial nephrotic syndrome	DISADF8G	Limited	Genetic Variation	[21]
Meckel syndrome, type 1	DIS4YWZU	Limited	Genetic Variation	[22]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Nephrocystin-1 (NPHP1).	[23]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Nephrocystin-1 (NPHP1).	[24]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Nephrocystin-1 (NPHP1).	[25]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Nephrocystin-1 (NPHP1).	[26]
Azacitidine	DMTA5OE	Approved	Azacitidine increases the expression of Nephrocystin-1 (NPHP1).	[27]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Nephrocystin-1 (NPHP1).	[29]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of Nephrocystin-1 (NPHP1).	[30]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Nephrocystin-1 (NPHP1).	[28]

References

• [1] 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.
• [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] Reassessing the pathogenicity of c.2858G>T(p.(G953V)) in COL4A5 Gene: report of 19 Chinese families.Eur J Hum Genet. 2020 Feb;28(2):244-252. doi: 10.1038/s41431-019-0523-1. Epub 2019 Oct 1.
• [4] Pooling/bootstrap-based GWAS (pbGWAS) identifies new loci modifying the age of onset in PSEN1 p.Glu280Ala Alzheimer's disease.Mol Psychiatry. 2013 May;18(5):568-75. doi: 10.1038/mp.2012.81. Epub 2012 Jun 19.
• [5] Fluorescence in situ hybridization for the diagnosis of NPHP1 deletion-related nephronophthisis on renal biopsy.Hum Pathol. 2018 Nov;81:71-77. doi: 10.1016/j.humpath.2018.06.021. Epub 2018 Jun 24.
• [6] Two novel homozygous mutations in NPHP1 lead to late onset end-stage renal disease: a case report of an adult nephronophthisis in a Chinese intermarriage family.BMC Nephrol. 2019 May 16;20(1):173. doi: 10.1186/s12882-019-1372-4.
• [7] Recurrent CNVs and SNVs at the NPHP1 locus contribute pathogenic alleles to Bardet-Biedl syndrome. Am J Hum Genet. 2014 May 1;94(5):745-54. doi: 10.1016/j.ajhg.2014.03.017. Epub 2014 Apr 17.
• [8] Clinical nosologic and genetic aspects of Joubert and related syndromes.J Child Neurol. 1999 Oct;14(10):660-6; discussion 669-72. doi: 10.1177/088307389901401007.
• [9] Genetic diagnosis in consanguineous families with kidney disease by homozygosity mapping coupled with whole-exome sequencing.Am J Kidney Dis. 2011 Aug;58(2):186-95. doi: 10.1053/j.ajkd.2011.01.025. Epub 2011 Jun 12.
• [10] DNA analysis of AHI1, NPHP1 and CYCLIN D1 in Joubert syndrome patients from the Netherlands.Eur J Med Genet. 2008 Jan-Feb;51(1):24-34. doi: 10.1016/j.ejmg.2007.10.001. Epub 2007 Oct 6.
• [11] 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.
• [12] Children with ocular motor apraxia type Cogan carry deletions in the gene (NPHP1) for juvenile nephronophthisis.J Pediatr. 2000 Jun;136(6):828-31.
• [13] Nephrocystin specifically localizes to the transition zone of renal and respiratory cilia and photoreceptor connecting cilia.J Am Soc Nephrol. 2006 Sep;17(9):2424-33. doi: 10.1681/ASN.2005121351. Epub 2006 Aug 2.
• [14] Genome-wide analysis of copy number variants in age-related macular degeneration.Hum Genet. 2011 Jan;129(1):91-100. doi: 10.1007/s00439-010-0904-6. Epub 2010 Oct 28.
• [15] A 11 Mb YAC-based contig spanning the familial juvenile nephronophthisis region (NPH1) located on chromosome 2q.Genomics. 1995 Dec 10;30(3):514-20. doi: 10.1006/geno.1995.1272.
• [16] NPHP1 (Nephrocystin-1) Gene Deletions Cause Adult-Onset ESRD.J Am Soc Nephrol. 2018 Jun;29(6):1772-1779. doi: 10.1681/ASN.2017111200. Epub 2018 Apr 13.
• [17] 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.
• [18] Antenatal Presentation of Wilms' Tumor.Urology. 2019 Dec;134:225-227. doi: 10.1016/j.urology.2019.08.011. Epub 2019 Aug 14.
• [19] Molecular karyotyping in patients with mental retardation using 100K single-nucleotide polymorphism arrays.J Med Genet. 2007 Oct;44(10):629-36. doi: 10.1136/jmg.2007.050914. Epub 2007 Jun 29.
• [20] Beneficial effects of astragalus polysaccharides treatment on cardiac chymase activities and cardiomyopathy in diabetic hamsters.Acta Diabetol. 2010 Dec;47 Suppl 1:35-46. doi: 10.1007/s00592-009-0116-5. Epub 2009 Apr 7.
• [21] Simultaneous mutations of LAMB2 and NPHP1genes in a Chinese girl with isolated congenital nephrotic syndrome: a case report.BMC Pediatr. 2016 Mar 22;16:44. doi: 10.1186/s12887-016-0583-0.
• [22] Novel transglutaminase-like peptidase and C2 domains elucidate the structure, biogenesis and evolution of the ciliary compartment.Cell Cycle. 2012 Oct 15;11(20):3861-75. doi: 10.4161/cc.22068. Epub 2012 Sep 14.
• [23] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [24] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [25] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [26] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [27] The effect of DNA methylation inhibitor 5-Aza-2'-deoxycytidine on human endometrial stromal cells. Hum Reprod. 2010 Nov;25(11):2859-69.
• [28] 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.
• [29] 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.
• [30] A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.