Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT7BMOYE)

• DOT Name: Complement factor H-related protein 5 (CFHR5)
• Synonyms: FHR-5
• Gene Name: CFHR5
• Related Disease:
  End-stage renal disease
  Fibronectin glomerulopathy
  Alport syndrome
  Atypical hemolytic uremic syndrome
  C3 glomerulonephritis
  Chronic kidney disease
  Chronic renal failure
  Dense deposit disease
  Dowling-Degos disease
  Glomerulonephritis
  Neovascular age-related macular degeneration
  Nephrotic syndrome
  Non-immunoglobulin-mediated membranoproliferative glomerulonephritis
  Rickettsiosis
  Systemic lupus erythematosus
  Complement deficiency
  Cholestasis
  Follicular lymphoma
  Hemolytic-uremic syndrome
  Kidney failure
  Lupus nephritis
  Streptococcus infection
• UniProt ID: FHR5_HUMAN
• Pfam ID: PF00084
• Sequence:
  MLLLFSVILISWVSTVGGEGTLCDFPKIHHGFLYDEEDYNPFSQVPTGEVFYYSCEYNFV
  SPSKSFWTRITCTEEGWSPTPKCLRMCSFPFVKNGHSESSGLIHLEGDTVQIICNTGYSL
  QNNEKNISCVERGWSTPPICSFTKGECHVPILEANVDAQPKKESYKVGDVLKFSCRKNLI
  RVGSDSVQCYQFGWSPNFPTCKGQVRSCGPPPQLSNGEVKEIRKEEYGHNEVVEYDCNPN
  FIINGPKKIQCVDGEWTTLPTCVEQVKTCGYIPELEYGYVQPSVPPYQHGVSVEVNCRNE
  YAMIGNNMITCINGIWTELPMCVATHQLKRCKIAGVNIKTLLKLSGKEFNHNSRIRYRCS
  DIFRYRHSVCINGKWNPEVDCTEKREQFCPPPPQIPNAQNMTTTVNYQDGEKVAVLCKEN
  YLLPEAKEIVCKDGRWQSLPRCVESTAYCGPPPSINNGDTTSFPLSVYPPGSTVTYRCQS
  FYKLQGSVTVTCRNKQWSEPPRCLDPCVVSEENMNKNNIQLKWRNDGKLYAKTGDAVEFQ
  CKFPHKAMISSPPFRAICQEGKFEYPICE
• Function: Involved in complement regulation. The dimerized forms have avidity for tissue-bound complement fragments and efficiently compete with the physiological complement inhibitor CFH.
• Tissue Specificity: Expressed by the liver and secreted in plasma.
• KEGG Pathway: Complement and coagulation cascades (hsa04610)
• Reactome Pathway: Regulation of Complement cascade (R-HSA-977606)

Molecular Interaction Atlas (MIA) of This DOT

22 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]
Fibronectin glomerulopathy	DISKTESP	Definitive	Biomarker	[2]
Alport syndrome	DIS25AB4	Strong	Genetic Variation	[3]
Atypical hemolytic uremic syndrome	DIS6FUDJ	Strong	Biomarker	[4]
C3 glomerulonephritis	DIS0KF9P	Strong	Autosomal dominant	[5]
Chronic kidney disease	DISW82R7	Strong	Genetic Variation	[1]
Chronic renal failure	DISGG7K6	Strong	Genetic Variation	[1]
Dense deposit disease	DISLWJSE	Strong	Genetic Variation	[4]
Dowling-Degos disease	DISGTTEP	Strong	Genetic Variation	[4]
Glomerulonephritis	DISPZIQ3	Strong	Genetic Variation	[6]
Neovascular age-related macular degeneration	DIS5S9R7	Strong	Genetic Variation	[7]
Nephrotic syndrome	DISSPSC2	Strong	Genetic Variation	[8]
Non-immunoglobulin-mediated membranoproliferative glomerulonephritis	DISLMV1J	Strong	Biomarker	[9]
Rickettsiosis	DIS4GUSE	Strong	Biomarker	[10]
Systemic lupus erythematosus	DISI1SZ7	Strong	Altered Expression	[11]
Complement deficiency	DISGN469	moderate	Biomarker	[12]
Cholestasis	DISDJJWE	Limited	Biomarker	[13]
Follicular lymphoma	DISVEUR6	Limited	Biomarker	[14]
Hemolytic-uremic syndrome	DISSCBGW	Limited	Genetic Variation	[15]
Kidney failure	DISOVQ9P	Limited	Biomarker	[16]
Lupus nephritis	DISCVGPZ	Limited	Biomarker	[11]
Streptococcus infection	DIS04U9T	Limited	Genetic Variation	[6]

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 Complement factor H-related protein 5 (CFHR5).	[17]

4 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 Complement factor H-related protein 5 (CFHR5).	[13]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Complement factor H-related protein 5 (CFHR5).	[19]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of Complement factor H-related protein 5 (CFHR5).	[20]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Complement factor H-related protein 5 (CFHR5).	[21]

References

• [1] A miR-1207-5p binding site polymorphism abolishes regulation of HBEGF and is associated with disease severity in CFHR5 nephropathy.PLoS One. 2012;7(2):e31021. doi: 10.1371/journal.pone.0031021. Epub 2012 Feb 2.
• [2] Frequent COL4 mutations in familial microhematuria accompanied by later-onset Alport nephropathy due to focal segmental glomerulosclerosis.Clin Genet. 2017 Nov;92(5):517-527. doi: 10.1111/cge.13077. Epub 2017 Sep 25.
• [3] Epistatic role of the MYH9/APOL1 region on familial hematuria genes.PLoS One. 2013;8(3):e57925. doi: 10.1371/journal.pone.0057925. Epub 2013 Mar 14.
• [4] Complement factor H related proteins (CFHRs). Mol Immunol. 2013 Dec 15;56(3):170-80. doi: 10.1016/j.molimm.2013.06.001. Epub 2013 Jul 3.
• [5] Mutations in alternative pathway complement proteins in American patients with atypical hemolytic uremic syndrome. Hum Mutat. 2010 Jun;31(6):E1445-60. doi: 10.1002/humu.21256.
• [6] Acute presentation and persistent glomerulonephritis following streptococcal infection in a patient with heterozygous complement factor H-related protein 5 deficiency.Am J Kidney Dis. 2012 Jul;60(1):121-5. doi: 10.1053/j.ajkd.2012.02.329. Epub 2012 Apr 13.
• [7] A large genome-wide association study of age-related macular degeneration highlights contributions of rare and common variants.Nat Genet. 2016 Feb;48(2):134-43. doi: 10.1038/ng.3448. Epub 2015 Dec 21.
• [8] A novel CFHR5 mutation associated with C3 glomerulonephritis in a Turkish girl.J Nephrol. 2014 Aug;27(4):457-60. doi: 10.1007/s40620-013-0008-1. Epub 2013 Dec 5.
• [9] FHR5 Binds to Laminins, Uses Separate C3b and Surface-Binding Sites, and Activates Complement on Malondialdehyde-Acetaldehyde Surfaces.J Immunol. 2018 Apr 1;200(7):2280-2290. doi: 10.4049/jimmunol.1701641. Epub 2018 Feb 26.
• [10] Does complement Factor H-Related protein 5 Nephropathy (Troodos Nephropathy) protect from rickettsial infections?.Med Hypotheses. 2017 Jan;98:76-80. doi: 10.1016/j.mehy.2016.11.018. Epub 2016 Nov 27.
• [11] The clinical significance of plasma CFHR 1-5 in lupus nephropathy.Immunobiology. 2019 May;224(3):339-346. doi: 10.1016/j.imbio.2019.03.005. Epub 2019 Apr 3.
• [12] Circulating complement factor H-related proteins 1and 5 correlate with disease activity in IgA nephropathy.Kidney Int. 2017 Oct;92(4):942-952. doi: 10.1016/j.kint.2017.03.043. Epub 2017 Jun 30.
• [13] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [14] Germline variation in complement genes and event-free survival in follicular and diffuse large B-cell lymphoma.Am J Hematol. 2012 Sep;87(9):880-5. doi: 10.1002/ajh.23273. Epub 2012 Jun 20.
• [15] Genetic analysis of the complement factor H related 5 gene in haemolytic uraemic syndrome.Mol Immunol. 2007 Mar;44(7):1704-8. doi: 10.1016/j.molimm.2006.08.004. Epub 2006 Sep 26.
• [16] A novel CFHR5 fusion protein causes C3 glomerulopathy in a family without Cypriot ancestry.Kidney Int. 2014 Apr;85(4):933-7. doi: 10.1038/ki.2013.348. Epub 2013 Sep 25.
• [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] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [19] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [20] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [21] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.