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Gene Review

CFH  -  complement factor H

Homo sapiens

Synonyms: AHUS1, AMBP1, ARMD4, ARMS1, CFHL3, ...
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Disease relevance of CFH

  • Several mutations in the CFH gene have been described in non-Shiga-toxin-associated haemolytic uraemic syndrome (non-Stx-HUS), a rare syndrome characterized by haemolytic anaemia, thrombocytopenia and acute renal failure [1].
  • Complement factor H polymorphism, complement activators, and risk of age-related macular degeneration [2].
  • Patients carrying MCP mutations have a favorable clinical outcome in comparison to those with factor H (CFH) or factor I (IF) mutations, which lead in most cases to end-stage renal failure [3].
  • Several recent studies have established an association between abnormalities of complement factor H (FH) and the development of hemolytic uremic syndrome (HUS) [4].
  • In the present study, using a mouse model of systemic infection and flow-cytometric analyses, we demonstrated an in vivo interaction between FH and pneumococci and showed differential FH binding during bacteremia [5].

Psychiatry related information on CFH

  • These findings suggest that blood may be a rich source for biomarkers of Alzheimer's disease and that CFH, together with other proteins such as alpha-2M may be a specific markers of this illness [6].
  • Here we describe a case of a woman who developed a sporadic form of TTP-HUS during a treatment with bupropion for smoking cessation, successfully treated with plasma ex-change therapy [7].

High impact information on CFH


Chemical compound and disease context of CFH

  • We have shown that complement factor H (CFH) interacts with HIV-1 at the level of the sequence Env 105-119, contained in the C1 domain of gp120 [12].
  • Very little is known about the effects of Ang II on sympathetic neurotransmission at the peripheral level in congestive heart failure (CFH) [13].
  • Deficiency of and mutations in the complement factor H (CFH) gene are associated with the development of MPGN II/DDD, suggesting that dysregulation of the alternative pathway of the complement cascade is important in disease pathophysiology [14].
  • Prednisone alone was judged to be effective in 30 patients with mild TTP-HUS (two relapses and two deaths) [11].
  • CONCLUSIONS: Quinine is a common cause of drug-associated TTP-HUS and can cause death and chronic renal failure [15].

Biological context of CFH

  • The CRP haplotypes conferring high levels of CRP significantly increased the effect of CFH Y402H (P<.01) [2].
  • OBJECTIVES: To assess the associations between the CFH gene and AMD in the general population and to investigate the modifying effect of smoking, serum inflammatory markers, and genetic variation of C-reactive protein (CRP) [2].
  • The plasma protein factor H (FH) inhibits the alternative pathway of complement activation [16].
  • A previous report demonstrated that a dominant form of HUS maps to chromosome 1q and that complement factor H (CFH), a regulatory component of the complement system, lies within the region and is involved in the dominant disorder [17].
  • Mutation analysis of the CFH coding region revealed a single missense mutation [17].

Anatomical context of CFH


Associations of CFH with chemical compounds

  • Finally, the interaction between rFHL-1 and purified M5 protein was inhibited by heparin, which binds FH via SCR 7 [16].
  • Previously we have shown that two members of the newly named SIBLING (small integrin-binding ligand, N-linked glycoproteins) family of proteins, bone sialoprotein, and osteopontin, bound first to a cell surface receptor and then to complement Factor H thereby blocking the lytic activity of the alternative pathway of complement [23].
  • Factor H (FH) is a potent suppressor of the alternative pathway of C in plasma and when bound to sialic acid- or glycosaminoglycan-rich surfaces [24].
  • The most documented risk-conferring single-nucleotide polymorphism results in a tyrosine-to-histidine substitution at position 402 (Y402H) of the CFH protein [22].
  • Association studies have identified a major risk variant within the complement factor H gene (CFH), and recent reports suggest that PLEKHA1/LOC387715 and the BF/C2 regions may be major risk loci for AMD as well [25].
  • The surface-expressed CaGpm1p is a virulence factor that utilizes the host Factor H, FHL-1, and plasminogen for immune evasion and degradation of extracellular matrices [26].

Physical interactions of CFH

  • Using the surface plasmon resonance technique and a panel of recombinantly expressed FH constructs, we observed that CRP binds to two closely located regions on short consensus repeat (SCR) domains 7 and 8-11 of FH [27].
  • In this report, we show that BSP and OPN form rapid and tight complexes with complement Factor H [28].
  • Complement factor H is a serum-binding protein for adrenomedullin, and the resulting complex modulates the bioactivities of both partners [29].
  • Based on the data presented here, we hypothesize that the primary function of FHL-1 binding by T. denticola might be to facilitate adherence to FHL-1 present on anchorage-dependent cells and in the extracellular matrix [30].

Regulatory relationships of CFH

  • Our results support the view that RPE cells synthesise and express CFH and are probably a major local source of this protein at the retina/choroid interface, secreting CFH into the interphotoreceptor matrix as well as Bruch's membrane [31].

Other interactions of CFH

  • In this study, we examined the interaction of CRP with factor H (FH), a key regulator of the alternative pathway (AP) of complement [27].
  • We screened CFHR5 gene for variations potentially involved in the aetiology of HUS [1].
  • The outcome of the disease reported here indicates that MCP mutation and complete paternal uniparental disomy of chromosome 1 could have an additive effect in determining the severity of the HUS phenotype [3].
  • Joint action of CFH and LOC387715 was best described by independent multiplicative effect without significant interaction in both cohorts [32].
  • Release of endogenous anti-inflammatory complement regulators FHL-1 and factor H protects synovial fibroblasts during rheumatoid arthritis [33].

Analytical, diagnostic and therapeutic context of CFH


  1. Genetic analysis of the complement factor H related 5 gene in haemolytic uraemic syndrome. Monteferrante, G., Brioschi, S., Caprioli, J., Pianetti, G., Bettinaglio, P., Bresin, E., Remuzzi, G., Noris, M. Mol. Immunol. (2007) [Pubmed]
  2. Complement factor H polymorphism, complement activators, and risk of age-related macular degeneration. Despriet, D.D., Klaver, C.C., Witteman, J.C., Bergen, A.A., Kardys, I., de Maat, M.P., Boekhoorn, S.S., Vingerling, J.R., Hofman, A., Oostra, B.A., Uitterlinden, A.G., Stijnen, T., van Duijn, C.M., de Jong, P.T. JAMA (2006) [Pubmed]
  3. Unusual clinical severity of complement membrane cofactor protein--associated hemolytic-uremic syndrome and uniparental isodisomy. Fremeaux-Bacchi, V., Sanlaville, D., Menouer, S., Blouin, J., Dragon-Durey, M.A., Fischbach, M., Vekemans, M., Fridman, W.H. Am. J. Kidney Dis. (2007) [Pubmed]
  4. Factor H mutations in hemolytic uremic syndrome cluster in exons 18-20, a domain important for host cell recognition. Richards, A., Buddles, M.R., Donne, R.L., Kaplan, B.S., Kirk, E., Venning, M.C., Tielemans, C.L., Goodship, J.A., Goodship, T.H. Am. J. Hum. Genet. (2001) [Pubmed]
  5. In vivo binding of complement regulator factor H by Streptococcus pneumoniae. Quin, L.R., Carmicle, S., Dave, S., Pangburn, M.K., Evenhuis, J.P., McDaniel, L.S. J. Infect. Dis. (2005) [Pubmed]
  6. Proteome-based plasma biomarkers for Alzheimer's disease. Hye, A., Lynham, S., Thambisetty, M., Causevic, M., Campbell, J., Byers, H.L., Hooper, C., Rijsdijk, F., Tabrizi, S.J., Banner, S., Shaw, C.E., Foy, C., Poppe, M., Archer, N., Hamilton, G., Powell, J., Brown, R.G., Sham, P., Ward, M., Lovestone, S. Brain (2006) [Pubmed]
  7. Thrombotic thrombocytopenic purpura-hemolytic uremic syndrome after bupropion treatment for smoking cessation. Mele, L., Voso, M.T., Fianchi, L., Leone, G., Pagano, L. Blood Coagul. Fibrinolysis (2003) [Pubmed]
  8. Corrigendum: A common CFH haplotype, with deletion of CFHR1 and CFHR3, is associated with lower risk of age-related macular degeneration. Hughes, A.E., Orr, N., Esfandiary, H., Diaz-Torres, M., Goodship, T., Chakravarthy, U. Nat. Genet. (2007) [Pubmed]
  9. A common CFH haplotype, with deletion of CFHR1 and CFHR3, is associated with lower risk of age-related macular degeneration. Hughes, A.E., Orr, N., Esfandiary, H., Diaz-Torres, M., Goodship, T., Chakravarthy, U. Nat. Genet. (2006) [Pubmed]
  10. Variation in factor B (BF) and complement component 2 (C2) genes is associated with age-related macular degeneration. Gold, B., Merriam, J.E., Zernant, J., Hancox, L.S., Taiber, A.J., Gehrs, K., Cramer, K., Neel, J., Bergeron, J., Barile, G.R., Smith, R.T., Hageman, G.S., Dean, M., Allikmets, R., Chang, S., Yannuzzi, L.A., Merriam, J.C., Barbazetto, I., Lerner, L.E., Russell, S., Hoballah, J., Hageman, J., Stockman, H. Nat. Genet. (2006) [Pubmed]
  11. Improved survival in thrombotic thrombocytopenic purpura-hemolytic uremic syndrome. Clinical experience in 108 patients. Bell, W.R., Braine, H.G., Ness, P.M., Kickler, T.S. N. Engl. J. Med. (1991) [Pubmed]
  12. HIV glycoprotein 41 and complement factor H interact with each other and share functional as well as antigenic homology. Pintér, C., Siccardi, A.G., Lopalco, L., Longhi, R., Clivio, A. AIDS Res. Hum. Retroviruses (1995) [Pubmed]
  13. Decreased facilitation by angiotensin II of noradrenergic neurotransmission in isolated mesenteric artery of rabbits with chronic heart failure. Balt, J.C., Belterman, C.N., Mathy, M.J., Nap, A., Baartscheer, A., Pfaffendorf, M., Van Zwieten, P.A. J. Cardiovasc. Pharmacol. (2003) [Pubmed]
  14. Variations in the complement regulatory genes factor H (CFH) and factor H related 5 (CFHR5) are associated with membranoproliferative glomerulonephritis type II (dense deposit disease). Abrera-Abeleda, M.A., Nishimura, C., Smith, J.L., Sethi, S., McRae, J.L., Murphy, B.F., Silvestri, G., Skerka, C., Józsi, M., Zipfel, P.F., Hageman, G.S., Smith, R.J. J. Med. Genet. (2006) [Pubmed]
  15. Quinine-associated thrombotic thrombocytopenic purpura-hemolytic uremic syndrome: frequency, clinical features, and long-term outcomes. Kojouri, K., Vesely, S.K., George, J.N. Ann. Intern. Med. (2001) [Pubmed]
  16. Identification of a domain in human factor H and factor H-like protein-1 required for the interaction with streptococcal M proteins. Kotarsky, H., Hellwage, J., Johnsson, E., Skerka, C., Svensson, H.G., Lindahl, G., Sjöbring, U., Zipfel, P.F. J. Immunol. (1998) [Pubmed]
  17. Complement factor H gene mutation associated with autosomal recessive atypical hemolytic uremic syndrome. Ying, L., Katz, Y., Schlesinger, M., Carmi, R., Shalev, H., Haider, N., Beck, G., Sheffield, V.C., Landau, D. Am. J. Hum. Genet. (1999) [Pubmed]
  18. A common haplotype in the complement regulatory gene factor H (HF1/CFH) predisposes individuals to age-related macular degeneration. Hageman, G.S., Anderson, D.H., Johnson, L.V., Hancox, L.S., Taiber, A.J., Hardisty, L.I., Hageman, J.L., Stockman, H.A., Borchardt, J.D., Gehrs, K.M., Smith, R.J., Silvestri, G., Russell, S.R., Klaver, C.C., Barbazetto, I., Chang, S., Yannuzzi, L.A., Barile, G.R., Merriam, J.C., Smith, R.T., Olsh, A.K., Bergeron, J., Zernant, J., Merriam, J.E., Gold, B., Dean, M., Allikmets, R. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  19. Binding of complement factor H to endothelial cells is mediated by the carboxy-terminal glycosaminoglycan binding site. Jokiranta, T.S., Cheng, Z.Z., Seeberger, H., Jòzsi, M., Heinen, S., Noris, M., Remuzzi, G., Ormsby, R., Gordon, D.L., Meri, S., Hellwage, J., Zipfel, P.F. Am. J. Pathol. (2005) [Pubmed]
  20. Recruitment of complement factor H-like protein 1 promotes intracellular invasion by group A streptococci. Pandiripally, V., Wei, L., Skerka, C., Zipfel, P.F., Cue, D. Infect. Immun. (2003) [Pubmed]
  21. Assignment of complement components C4 binding protein (C4BP) and factor H (FH) to human chromosome 1q, using cDNA probes. Hing, S., Day, A.J., Linton, S.J., Ripoche, J., Sim, R.B., Reid, K.B., Solomon, E. Ann. Hum. Genet. (1988) [Pubmed]
  22. Individuals homozygous for the age-related macular degeneration risk-conferring variant of complement factor H have elevated levels of CRP in the choroid. Johnson, P.T., Betts, K.E., Radeke, M.J., Hageman, G.S., Anderson, D.H., Johnson, L.V. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  23. Three SIBLINGs (small integrin-binding ligand, N-linked glycoproteins) enhance factor H's cofactor activity enabling MCP-like cellular evasion of complement-mediated attack. Jain, A., Karadag, A., Fohr, B., Fisher, L.W., Fedarko, N.S. J. Biol. Chem. (2002) [Pubmed]
  24. Complement C3b/C3d and cell surface polyanions are recognized by overlapping binding sites on the most carboxyl-terminal domain of complement factor H. Hellwage, J., Jokiranta, T.S., Friese, M.A., Wolk, T.U., Kampen, E., Zipfel, P.F., Meri, S. J. Immunol. (2002) [Pubmed]
  25. The genetics of age-related macular degeneration: a review of progress to date. Haddad, S., Chen, C.A., Santangelo, S.L., Seddon, J.M. Survey of ophthalmology. (2006) [Pubmed]
  26. Gpm1p is a factor H-, FHL-1-, and plasminogen-binding surface protein of Candida albicans. Poltermann, S., Kunert, A., von der Heide, M., Eck, R., Hartmann, A., Zipfel, P.F. J. Biol. Chem. (2007) [Pubmed]
  27. Regulation of complement activation by C-reactive protein: targeting the complement inhibitory activity of factor H by an interaction with short consensus repeat domains 7 and 8-11. Jarva, H., Jokiranta, T.S., Hellwage, J., Zipfel, P.F., Meri, S. J. Immunol. (1999) [Pubmed]
  28. Factor H binding to bone sialoprotein and osteopontin enables tumor cell evasion of complement-mediated attack. Fedarko, N.S., Fohr, B., Robey, P.G., Young, M.F., Fisher, L.W. J. Biol. Chem. (2000) [Pubmed]
  29. Complement factor H is a serum-binding protein for adrenomedullin, and the resulting complex modulates the bioactivities of both partners. Pio, R., Martinez, A., Unsworth, E.J., Kowalak, J.A., Bengoechea, J.A., Zipfel, P.F., Elsasser, T.H., Cuttitta, F. J. Biol. Chem. (2001) [Pubmed]
  30. Demonstration of factor H-like protein 1 binding to Treponema denticola, a pathogen associated with periodontal disease in humans. McDowell, J.V., Lankford, J., Stamm, L., Sadlon, T., Gordon, D.L., Marconi, R.T. Infect. Immun. (2005) [Pubmed]
  31. Synthesis of complement factor H by retinal pigment epithelial cells is down-regulated by oxidized photoreceptor outer segments. Chen, M., Forrester, J.V., Xu, H. Exp. Eye Res. (2007) [Pubmed]
  32. CFH, ELOVL4, PLEKHA1 and LOC387715 genes and susceptibility to age-related maculopathy: AREDS and CHS cohorts and meta-analyses. Conley, Y.P., Jakobsdottir, J., Mah, T., Weeks, D.E., Klein, R., Kuller, L., Ferrell, R.E., Gorin, M.B. Hum. Mol. Genet. (2006) [Pubmed]
  33. Release of endogenous anti-inflammatory complement regulators FHL-1 and factor H protects synovial fibroblasts during rheumatoid arthritis. Friese, M.A., Manuelian, T., Junnikkala, S., Hellwage, J., Meri, S., Peter, H.H., Gordon, D.L., Eibel, H., Zipfel, P.F. Clin. Exp. Immunol. (2003) [Pubmed]
  34. Complement factor H polymorphisms in Japanese population with age-related macular degeneration. Okamoto, H., Umeda, S., Obazawa, M., Minami, M., Noda, T., Mizota, A., Honda, M., Tanaka, M., Koyama, R., Takagi, I., Sakamoto, Y., Saito, Y., Miyake, Y., Iwata, T. Mol. Vis. (2006) [Pubmed]
  35. Complement factor H deficiency in acute allograft glomerulopathy and post-transplant hemolytic uremic syndrome. Fortin, M.C., Schürch, W., Cardinal, H., Hébert, M.J. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons. (2004) [Pubmed]
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