Pediatric Nephrology

, Volume 25, Issue 12, pp 2431–2442

Genetics and complement in atypical HUS

Educational Review

Abstract

Central to the pathogenesis of atypical hemolytic uremic syndrome (aHUS) is over-activation of the alternative pathway of complement. Following the initial discovery of mutations in the complement regulatory protein, factor H, mutations have been described in factor I, membrane cofactor protein and thrombomodulin, which also result in decreased complement regulation. Autoantibodies to factor H have also been reported to impair complement regulation in aHUS. More recently, gain of function mutations in the complement components C3 and Factor B have been seen. This review focuses on the genetic causes of aHUS, their functional consequences, and clinical effect.

Keywords

Hemolytic uremic syndrome Transplantation Complement Factor H Factor I Membrane cofactor protein Thrombomodulin Thrombotic thrombocytopenic purpura 

Abbreviations

HUS

Hemolytic uremic syndrome

D+ve HUS

Diarrhoeal-associated hemolytic uremic syndrome

aHUS

Atypical hemolytic uremic syndrome

AP

Alternative pathway

CP

Classical pathway

CCPs

Complement control protein modules

RCA

Regulators of complement activation

ESRF

End-stage renal failure

SNPs

Single nucleotide polymorphisms

References

  1. 1.
    Kavanagh D, Richards A, Atkinson J (2008) Complement regulatory genes and hemolytic uremic syndromes. Annu Rev Med 59:293–309CrossRefPubMedGoogle Scholar
  2. 2.
    Fogo A, Kashgarian M (2005) Diagnostic atlas of renal pathology. Elsevier Science, AmsterdamGoogle Scholar
  3. 3.
    Tarr PI, Gordon CA, Chandler WL (2005) Shiga-toxin-producing Escherichia coli and haemolytic uraemic syndrome. Lancet 365:1073–1086PubMedGoogle Scholar
  4. 4.
    Noris M, Remuzzi G (2005) Hemolytic uremic syndrome. J Am Soc Nephrol 16:1035–1050CrossRefPubMedGoogle Scholar
  5. 5.
    Ariceta G, Besbas N, Johnson S, Karpman D, Landau D, Licht C, Loirat C, Pecoraro C, Taylor CM, Van de Kar N, Vandewalle J, Zimmerhackl LB (2009) Guideline for the investigation and initial therapy of diarrhea-negative hemolytic uremic syndrome. Pediatr Nephrol 24:687–696CrossRefPubMedGoogle Scholar
  6. 6.
    Rodriguez de Cordoba S, Esparza-Gordillo J, Goicoechea de Jorge E, Lopez-Trascasa M, Sanchez-Corral P (2004) The human complement factor H: functional roles, genetic variations and disease associations. Mol Immunol 41:355–367CrossRefPubMedGoogle Scholar
  7. 7.
    Richards A, Kavanagh D, Atkinson JP (2007) Inherited complement regulatory protein deficiency predisposes to human disease in acute injury and chronic inflammatory states: the examples of vascular damage in atypical hemolytic uremic syndrome and debris accumulation in age-related macular degeneration. Adv Immunol 96:141–177CrossRefPubMedGoogle Scholar
  8. 8.
    Hocking HG, Herbert AP, Kavanagh D, Soares DC, Ferreira VP, Pangburn MK, Uhrin D, Barlow PN (2008) Structure of the N-terminal region of complement factor H and conformational implications of disease-linked sequence variations. J Biol Chem 283:9475–9487CrossRefPubMedGoogle Scholar
  9. 9.
    Schmidt CQ, Herbert AP, Kavanagh D, Gandy C, Fenton CJ, Blaum BS, Lyon M, Uhrin D, Barlow PN (2008) A new map of glycosaminoglycan and C3b binding sites on factor H. J Immunol 181:2610–2619PubMedGoogle Scholar
  10. 10.
    Warwicker P, Goodship TH, Donne RL, Pirson Y, Nicholls A, Ward RM, Turnpenny P, Goodship JA (1998) Genetic studies into inherited and sporadic hemolytic uremic syndrome. Kidney Int 53:836–844CrossRefPubMedGoogle Scholar
  11. 11.
    Richards A, Buddles MR, Donne RL, Kaplan BS, Kirk E, Venning MC, Tielemans CL, Goodship JA, Goodship TH (2001) Factor H mutations in hemolytic uremic syndrome cluster in exons 18–20, a domain important for host cell recognition. Am J Hum Genet 68:485–490CrossRefPubMedGoogle Scholar
  12. 12.
    Dragon-Durey MA, Fremeaux-Bacchi V, Loirat C, Blouin J, Niaudet P, Deschenes G, Coppo P, Herman Fridman W, Weiss L (2004) Heterozygous and homozygous factor H deficiencies associated with hemolytic uremic syndrome or membranoproliferative glomerulonephritis: report and genetic analysis of 16 cases. J Am Soc Nephrol 15:787–795CrossRefPubMedGoogle Scholar
  13. 13.
    Caprioli J, Noris M, Brioschi S, Pianetti G, Castelletti F, Bettinaglio P, Mele C, Bresin E, Cassis L, Gamba S, Porrati F, Bucchioni S, Monteferrante G, Fang CJ, Liszewski MK, Kavanagh D, Atkinson JP, Remuzzi G (2006) Genetics of HUS: the impact of MCP, CFH, and IF mutations on clinical presentation, response to treatment, and outcome. Blood 108:1267–1279CrossRefPubMedGoogle Scholar
  14. 14.
    Neumann HP, Salzmann M, Bohnert-Iwan B, Mannuelian T, Skerka C, Lenk D, Bender BU, Cybulla M, Riegler P, Konigsrainer A, Neyer U, Bock A, Widmer U, Male DA, Franke G, Zipfel PF (2003) Haemolytic uraemic syndrome and mutations of the factor H gene: a registry-based study of German-speaking countries. J Med Genet 40:676–681CrossRefPubMedGoogle Scholar
  15. 15.
    Perez-Caballero D, Gonzalez-Rubio C, Gallardo ME, Vera M, Lopez-Trascasa M, Rodriguez de Cordoba S, Sanchez-Corral P (2001) Clustering of missense mutations in the C-terminal region of factor H in atypical hemolytic uremic syndrome. Am J Hum Genet 68:478–484CrossRefPubMedGoogle Scholar
  16. 16.
    Westra D, Volokhina E, van der Heijden E, Vos A, Huigen M, Jansen J, van Kaauwen E, van der Velden T, van de Kar N, van den Heuvel L (2010) Genetic disorders in complement (regulating) genes in patients with atypical haemolytic uraemic syndrome (aHUS). Nephrol Dial Transplant. doi:10.1093/ndt/gfq010 PubMedGoogle Scholar
  17. 17.
    Heinen S, Sanchez-Corral P, Jackson MS, Strain L, Goodship JA, Kemp EJ, Skerka C, Jokiranta TS, Meyers K, Wagner E, Robitaille P, Esparza-Gordillo J, Rodriguez de Cordoba S, Zipfel PF, Goodship TH (2006) De novo gene conversion in the RCA gene cluster (1q32) causes mutations in complement factor H associated with atypical hemolytic uremic syndrome. Hum Mutat 27:292–293CrossRefPubMedGoogle Scholar
  18. 18.
    Venables JP, Strain L, Routledge D, Bourn D, Powell HM, Warwicker P, Diaz-Torres ML, Sampson A, Mead P, Webb M, Pirson Y, Jackson MS, Hughes A, Wood KM, Goodship JA, Goodship TH (2006) Atypical haemolytic uraemic syndrome associated with a hybrid complement gene. PLoS Med 3:e431CrossRefPubMedGoogle Scholar
  19. 19.
    Ferreira VP, Herbert AP, Cortes C, McKee KA, Blaum BS, Esswein ST, Uhrin D, Barlow PN, Pangburn MK, Kavanagh D (2009) The binding of factor H to a complex of physiological polyanions and C3b on cells is impaired in atypical hemolytic uremic syndrome. J Immunol 182:7009–7018CrossRefPubMedGoogle Scholar
  20. 20.
    Sanchez-Corral P, Gonzalez-Rubio C, Rodriguez de Cordoba S, Lopez-Trascasa M (2004) Functional analysis in serum from atypical hemolytic uremic syndrome patients reveals impaired protection of host cells associated with mutations in factor H. Mol Immunol 41:81–84CrossRefPubMedGoogle Scholar
  21. 21.
    Abarrategui-Garrido C, Melgosa M, Pena-Carrion A, de Jorge EG, de Cordoba SR, Lopez-Trascasa M, Sanchez-Corral P (2008) Mutations in proteins of the alternative pathway of complement and the pathogenesis of atypical hemolytic uremic syndrome. Am J Kidney Dis 52:171–180CrossRefPubMedGoogle Scholar
  22. 22.
    Vaziri-Sani F, Holmberg L, Sjoholm AG, Kristoffersson AC, Manea M, Fremeaux-Bacchi V, Fehrman-Ekholm I, Raafat R, Karpman D (2006) Phenotypic expression of factor H mutations in patients with atypical hemolytic uremic syndrome. Kidney Int 69:981–988CrossRefPubMedGoogle Scholar
  23. 23.
    Stahl AL, Vaziri-Sani F, Heinen S, Kristoffersson AC, Gydell KH, Raafat R, Gutierrez A, Beringer O, Zipfel PF, Karpman D (2008) Factor H dysfunction in patients with atypical hemolytic uremic syndrome contributes to complement deposition on platelets and their activation. Blood 111:5307–5315CrossRefPubMedGoogle Scholar
  24. 24.
    Heinen S, Jozsi M, Hartmann A, Noris M, Remuzzi G, Skerka C, Zipfel PF (2007) Hemolytic uremic syndrome: a factor H mutation (E1172Stop) causes defective complement control at the surface of endothelial cells. J Am Soc Nephrol 18:506–514CrossRefPubMedGoogle Scholar
  25. 25.
    Nan R, Gor J, Perkins SJ (2008) Implications of the progressive self-association of wild-type human factor H for complement regulation and disease. J Mol Biol 375:891–900CrossRefPubMedGoogle Scholar
  26. 26.
    Pangburn MK, Rawal N, Cortes C, Alam MN, Ferreira VP, Atkinson MA (2009) Polyanion-induced self-association of complement factor H. J Immunol 182:1061–1068PubMedGoogle Scholar
  27. 27.
    Okemefuna AI, Li K, Nan R, Ormsby RJ, Sadlon T, Gordon DL, Perkins SJ (2009) Multimeric interactions between complement factor H and its C3d ligand provide new insight on complement regulation. J Mol Biol 391:119–135CrossRefPubMedGoogle Scholar
  28. 28.
    Richards A, Kavanagh D (2009) Pathogenesis of thrombotic microangiopathy: insights from animal models. Nephron Exp Nephrol 113:e97–e103CrossRefPubMedGoogle Scholar
  29. 29.
    Pickering MC, Cook HT, Warren J, Bygrave AE, Moss J, Walport MJ, Botto M (2002) Uncontrolled C3 activation causes membranoproliferative glomerulonephritis in mice deficient in complement factor H. Nat Genet 31:424–428PubMedGoogle Scholar
  30. 30.
    Hegasy GA, Manuelian T, Hogasen K, Jansen JH, Zipfel PF (2002) The molecular basis for hereditary porcine membranoproliferative glomerulonephritis type II: point mutations in the factor H coding sequence block protein secretion. Am J Pathol 161:2027–2034PubMedGoogle Scholar
  31. 31.
    Pickering MC, de Jorge EG, Martinez-Barricarte R, Recalde S, Garcia-Layana A, Rose KL, Moss J, Walport MJ, Cook HT, de Cordoba SR, Botto M (2007) Spontaneous hemolytic uremic syndrome triggered by complement factor H lacking surface recognition domains. J Exp Med 204:1249–1256CrossRefPubMedGoogle Scholar
  32. 32.
    Goicoechea de Jorge E, Paixao-Cavalcante D, Rose K, Cook H, Botto M, Pickering M (2008) C5 activation is required for the development of atypical haemolytic uraemic syndrome in Cfh-/-FH Delta 16–20 mice. Mol Immunol 44:4100Google Scholar
  33. 33.
    Richards A, Kathryn Liszewski M, Kavanagh D, Fang CJ, Moulton E, Fremeaux-Bacchi V, Remuzzi G, Noris M, Goodship TH, Atkinson JP (2007) Implications of the initial mutations in membrane cofactor protein (MCP; CD46) leading to atypical hemolytic uremic syndrome. Mol Immunol 44:111–122CrossRefPubMedGoogle Scholar
  34. 34.
    Richards A, Kemp EJ, Liszewski MK, Goodship JA, Lampe AK, Decorte R, Muslumanoglu MH, Kavukcu S, Filler G, Pirson Y, Wen LS, Atkinson JP, Goodship TH (2003) Mutations in human complement regulator, membrane cofactor protein (CD46), predispose to development of familial hemolytic uremic syndrome. Proc Natl Acad Sci USA 100:12966–12971CrossRefPubMedGoogle Scholar
  35. 35.
    Fremeaux-Bacchi V, Moulton EA, Kavanagh D, Dragon-Durey MA, Blouin J, Caudy A, Arzouk N, Cleper R, Francois M, Guest G, Pourrat J, Seligman R, Fridman WH, Loirat C, Atkinson JP (2006) Genetic and functional analyses of membrane cofactor protein (CD46) mutations in atypical hemolytic uremic syndrome. J Am Soc Nephrol 17:2017–2025CrossRefPubMedGoogle Scholar
  36. 36.
    Noris M, Brioschi S, Caprioli J, Todeschini M, Bresin E, Porrati F, Gamba S, Remuzzi G (2003) Familial haemolytic uraemic syndrome and an MCP mutation. Lancet 362:1542–1547CrossRefPubMedGoogle Scholar
  37. 37.
    Sullivan M, Erlic Z, Hoffmann MM, Arbeiter K, Patzer L, Budde K, Hoppe B, Zeier M, Lhotta K, Rybicki LA, Bock A, Berisha G, Neumann HP (2010) Epidemiological approach to identifying genetic predispositions for atypical hemolytic uremic syndrome. Ann Hum Genet 74:17–26CrossRefPubMedGoogle Scholar
  38. 38.
    Fang CJ, Fremeaux-Bacchi V, Liszewski MK, Pianetti G, Noris M, Goodship TH, Atkinson JP (2008) Membrane cofactor protein mutations in atypical hemolytic uremic syndrome (aHUS), fatal Stx-HUS, C3 glomerulonephritis, and the HELLP syndrome. Blood 111:624–632CrossRefPubMedGoogle Scholar
  39. 39.
    Pangburn MK, Schreiber RD, Muller-Eberhard HJ (1977) Human complement C3b inactivator: isolation, characterization, and demonstration of an absolute requirement for the serum protein beta1H for cleavage of C3b and C4b in solution. J Exp Med 146:257–270CrossRefPubMedGoogle Scholar
  40. 40.
    Whaley K, Ruddy S (1976) Modulation of C3b hemolytic activity by a plasma protein distinct from C3b inactivator. Science 193:1011–1013CrossRefPubMedGoogle Scholar
  41. 41.
    Nagasawa S, Stroud RM (1977) Mechanism of action of the C3b inactivator: requirement for a high molecular weight cofactor (C3b-C4bINA cofactor) and production of a new C3b derivative (C3b′). Immunochemistry 14:749–756CrossRefPubMedGoogle Scholar
  42. 42.
    Shiraishi S, Stroud RM (1975) Cleavage products of C4b produced by enzymes in human serum. Immunochemistry 12:935–939CrossRefPubMedGoogle Scholar
  43. 43.
    Liszewski MK, Post TW, Atkinson JP (1991) Membrane cofactor protein (MCP or CD46): newest member of the regulators of complement activation gene cluster. Annu Rev Immunol 9:431–455CrossRefPubMedGoogle Scholar
  44. 44.
    Medof ME, Iida K, Mold C, Nussenzweig V (1982) Unique role of the complement receptor CR1 in the degradation of C3b associated with immune complexes. J Exp Med 156:1739–1754CrossRefPubMedGoogle Scholar
  45. 45.
    Ross GD, Lambris JD, Cain JA, Newman SL (1982) Generation of three different fragments of bound C3 with purified factor I or serum. I. Requirements for factor H vs. CR1 cofactor activity. J Immunol 129:2051–2060PubMedGoogle Scholar
  46. 46.
    Kavanagh D, Kemp EJ, Mayland E, Winney RJ, Duffield JS, Warwick G, Richards A, Ward R, Goodship JA, Goodship TH (2005) Mutations in complement factor I predispose to development of atypical hemolytic uremic syndrome. J Am Soc Nephrol 16:2150–2155CrossRefPubMedGoogle Scholar
  47. 47.
    Kavanagh D, Richards A, Noris M, Hauhart R, Liszewski MK, Karpman D, Goodship JA, Fremeaux-Bacchi V, Remuzzi G, Goodship TH, Atkinson JP (2008) Characterization of mutations in complement factor I (CFI) associated with hemolytic uremic syndrome. Mol Immunol 45:95–105CrossRefPubMedGoogle Scholar
  48. 48.
    Fremeaux-Bacchi V, Dragon-Durey MA, Blouin J, Vigneau C, Kuypers D, Boudailliez B, Loirat C, Rondeau E, Fridman WH (2004) Complement factor I: a susceptibility gene for atypical haemolytic uraemic syndrome. J Med Genet 41:e84CrossRefPubMedGoogle Scholar
  49. 49.
    Sellier-Leclerc AL, Fremeaux-Bacchi V, Dragon-Durey MA, Macher MA, Niaudet P, Guest G, Boudailliez B, Bouissou F, Deschenes G, Gie S, Tsimaratos M, Fischbach M, Morin D, Nivet H, Alberti C, Loirat C (2007) Differential impact of complement mutations on clinical characteristics in atypical hemolytic uremic syndrome. J Am Soc Nephrol 18:2392–2400CrossRefPubMedGoogle Scholar
  50. 50.
    Bienaime F, Dragon-Durey MA, Regnier CH, Nilsson SC, Kwan WH, Blouin J, Jablonski M, Renault N, Rameix-Welti MA, Loirat C, Sautes-Fridman C, Villoutreix BO, Blom AM, Fremeaux-Bacchi V (2010) Mutations in components of complement influence the outcome of factor I-associated atypical hemolytic uremic syndrome. Kidney Int 77:339–349CrossRefPubMedGoogle Scholar
  51. 51.
    de Paula PF, Barbosa JE, Junior PR, Ferriani VP, Latorre MR, Nudelman V, Isaac L (2003) Ontogeny of complement regulatory proteins—concentrations of factor h, factor I, c4b-binding protein, properdin and vitronectin in healthy children of different ages and in adults. Scand J Immunol 58:572–577CrossRefPubMedGoogle Scholar
  52. 52.
    Nilsson SC, Kalchishkova N, Trouw LA, Fremeaux-Bacchi V, Villoutreix BO, Blom AM (2010) Mutations in complement factor I as found in atypical hemolytic uremic syndrome lead to either altered secretion or altered function of factor I. Eur J Immunol 40:172–185CrossRefPubMedGoogle Scholar
  53. 53.
    Nilsson SC, Karpman D, Vaziri-Sani F, Kristoffersson AC, Salomon R, Provot F, Fremeaux-Bacchi V, Trouw LA, Blom AM (2007) A mutation in factor I that is associated with atypical hemolytic uremic syndrome does not affect the function of factor I in complement regulation. Mol Immunol 44:1835–1844CrossRefPubMedGoogle Scholar
  54. 54.
    Weiler H, Isermann BH (2003) Thrombomodulin. J Thromb Haemost 1:1515–1524CrossRefPubMedGoogle Scholar
  55. 55.
    Delvaeye M, Noris M, De Vriese A, Esmon CT, Esmon NL, Ferrell G, Del-Favero J, Plaisance S, Claes B, Lambrechts D, Zoja C, Remuzzi G, Conway EM (2009) Thrombomodulin mutations in atypical hemolytic-uremic syndrome. N Engl J Med 361:345–357CrossRefPubMedGoogle Scholar
  56. 56.
    Goicoechea de Jorge E, Harris CL, Esparza-Gordillo J, Carreras L, Arranz EA, Garrido CA, Lopez-Trascasa M, Sanchez-Corral P, Morgan BP, Rodriguez de Cordoba S (2007) Gain-of-function mutations in complement factor B are associated with atypical hemolytic uremic syndrome. Proc Natl Acad Sci USA 104:240–245CrossRefPubMedGoogle Scholar
  57. 57.
    Kavanagh D, Kemp EJ, Richards A, Burgess RM, Mayland E, Goodship JA, Goodship TH (2006) Does complement factor B have a role in the pathogenesis of atypical HUS? Mol Immunol 43:856–859CrossRefPubMedGoogle Scholar
  58. 58.
    Roumenina LT, Jablonski M, Hue C, Blouin J, Dimitrov JD, Dragon-Durey MA, Cayla M, Fridman WH, Macher MA, Ribes D, Moulonguet L, Rostaing L, Satchell SC, Mathieson PW, Sautes-Fridman C, Loirat C, Regnier CH, Halbwachs-Mecarelli L, Fremeaux-Bacchi V (2009) Hyperfunctional C3 convertase leads to complement deposition on endothelial cells and contributes to atypical hemolytic uremic syndrome. Blood 114:2837–2845PubMedGoogle Scholar
  59. 59.
    Lhotta K, Janecke AR, Scheiring J, Petzlberger B, Giner T, Fally V, Wurzner R, Zimmerhackl LB, Mayer G, Fremeaux-Bacchi V (2009) A large family with a gain-of-function mutation of complement C3 predisposing to atypical hemolytic uremic syndrome, microhematuria, hypertension and chronic renal failure. Clin J Am Soc Nephrol 4:1356–1362CrossRefPubMedGoogle Scholar
  60. 60.
    Fremeaux-Bacchi V, Miller EC, Liszewski MK, Strain L, Blouin J, Brown AL, Moghal N, Kaplan BS, Weiss RA, Lhotta K, Kapur G, Mattoo T, Nivet H, Wong W, Gie S, de Ligny BH, Fischbach M, Gupta R, Hauhart R, Meunier V, Loirat C, Dragon-Durey MA, Fridman WH, Janssen BJ, Goodship TH, Atkinson JP (2008) Mutations in complement C3 predispose to development of atypical hemolytic uremic syndrome. Blood 112:4948–4952CrossRefPubMedGoogle Scholar
  61. 61.
    Moore I, Strain L, Pappworth I, Kavanagh D, Barlow PN, Herbert AP, Schmidt CQ, Staniforth S, Holmes L, Ward R, Morgan L, Goodship TH, Marchbank K (2010) Association of factor H autoantibodies with deletions of CFHR1, CFHR3, CFHR4 and with mutations in CFH, CFI, CD46 and C3 in patients with atypical haemolytic uraemic syndrome. Blood. doi:10.1182/blood-2009-05-221549 Google Scholar
  62. 62.
    Abarrategui-Garrido C, Martinez-Barricarte R, Lopez-Trascasa M, Rodriguez de Cordoba S, Sanchez-Corral P (2009) Characterization of complement factor H-related (CFHR) proteins in plasma reveals novel genetic variations of CFHR1 associated with atypical hemolytic uremic syndrome. Blood 114:4261–4271CrossRefPubMedGoogle Scholar
  63. 63.
    Dragon-Durey MA, Loirat C, Cloarec S, Macher MA, Blouin J, Nivet H, Weiss L, Fridman WH, Fremeaux-Bacchi V (2005) Anti-Factor H autoantibodies associated with atypical hemolytic uremic syndrome. J Am Soc Nephrol 16:555–563CrossRefPubMedGoogle Scholar
  64. 64.
    Jozsi M, Licht C, Strobel S, Zipfel SL, Richter H, Heinen S, Zipfel PF, Skerka C (2008) Factor H autoantibodies in atypical hemolytic uremic syndrome correlate with CFHR1/CFHR3 deficiency. Blood 111:1512–1514CrossRefPubMedGoogle Scholar
  65. 65.
    Jozsi M, Strobel S, Dahse HM, Liu WS, Hoyer PF, Oppermann M, Skerka C, Zipfel PF (2007) Anti factor H autoantibodies block C-terminal recognition function of factor H in hemolytic uremic syndrome. Blood 110:1516–1518CrossRefPubMedGoogle Scholar
  66. 66.
    Zipfel PF, Edey M, Heinen S, Jozsi M, Richter H, Misselwitz J, Hoppe B, Routledge D, Strain L, Hughes AE, Goodship JA, Licht C, Goodship TH, Skerka C (2007) Deletion of complement factor H-related genes CFHR1 and CFHR3 is associated with atypical hemolytic uremic syndrome. PLoS Genet 3:e41CrossRefPubMedGoogle Scholar
  67. 67.
    Stahl AL, Kristoffersson A, Olin AI, Olsson ML, Roodhooft AM, Proesmans W, Karpman D (2009) A novel mutation in the complement regulator clusterin in recurrent hemolytic uremic syndrome. Mol Immunol 46:2236–2243CrossRefPubMedGoogle Scholar
  68. 68.
    Jenne DE, Tschopp J (1992) Clusterin: the intriguing guises of a widely expressed glycoprotein. Trends Biochem Sci 17:154–159CrossRefPubMedGoogle Scholar
  69. 69.
    Tschopp J, Jenne DE, Hertig S, Preissner KT, Morgenstern H, Sapino AP, French L (1993) Human megakaryocytes express clusterin and package it without apolipoprotein A-1 into alpha-granules. Blood 82:118–125PubMedGoogle Scholar
  70. 70.
    Rodriguez de Cordoba S (2010) aHUS: a disorder with many risk factors. Blood 115:158–160CrossRefPubMedGoogle Scholar
  71. 71.
    Kavanagh D, Burgess R, Spitzer D, Richards A, Diaz-Torres ML, Goodship JA, Hourcade DE, Atkinson JP, Goodship TH (2007) The decay accelerating factor mutation I197V found in hemolytic uraemic syndrome does not impair complement regulation. Mol Immunol 44:3162–3167CrossRefPubMedGoogle Scholar
  72. 72.
    Monteferrante G, Brioschi S, Caprioli J, Pianetti G, Bettinaglio P, Bresin E, Remuzzi G, Noris M (2007) Genetic analysis of the complement factor H-related 5 gene in haemolytic uraemic syndrome. Mol Immunol 44:1704–1708CrossRefPubMedGoogle Scholar
  73. 73.
    Fremeaux-Bacchi V, Kemp EJ, Goodship JA, Dragon-Durey MA, Strain L, Loirat C, Deng HW, Goodship TH (2005) The development of atypical haemolytic-uraemic syndrome is influenced by susceptibility factors in factor H and membrane cofactor protein: evidence from two independent cohorts. J Med Genet 42:852–856CrossRefPubMedGoogle Scholar
  74. 74.
    Esparza-Gordillo J, Goicoechea de Jorge E, Buil A, Carreras Berges L, Lopez-Trascasa M, Sanchez-Corral P, Rodriguez de Cordoba S (2005) Predisposition to atypical hemolytic uremic syndrome involves the concurrence of different susceptibility alleles in the regulators of complement activation gene cluster in 1q32. Hum Mol Genet 14:703–712CrossRefPubMedGoogle Scholar
  75. 75.
    Esparza-Gordillo J, Jorge EG, Garrido CA, Carreras L, Lopez-Trascasa M, Sanchez-Corral P, de Cordoba SR (2006) Insights into hemolytic uremic syndrome: segregation of three independent predisposition factors in a large, multiple affected pedigree. Mol Immunol 43:1769–1775CrossRefPubMedGoogle Scholar
  76. 76.
    Martinez-Barricarte R, Pianetti G, Gautard R, Misselwitz J, Strain L, Fremeaux-Bacchi V, Skerka C, Zipfel PF, Goodship T, Noris M, Remuzzi G, de Cordoba SR (2008) The complement factor H R1210C mutation is associated with atypical hemolytic uremic syndrome. J Am Soc Nephrol 19:639–646CrossRefPubMedGoogle Scholar
  77. 77.
    Blom AM, Bergstrom F, Edey M, Diaz-Torres M, Kavanagh D, Lampe A, Goodship JA, Strain L, Moghal N, McHugh M, Inward C, Tomson C, Fremeaux-Bacchi V, Villoutreix BO, Goodship TH (2008) A novel non-synonymous polymorphism (p.Arg240His) in C4b-binding protein is associated with atypical hemolytic uremic syndrome and leads to impaired alternative pathway cofactor activity. J Immunol 180:6385–6391PubMedGoogle Scholar
  78. 78.
    Tortajada A, Montes T, Martinez-Barricarte R, Morgan BP, Harris CL, de Cordoba SR (2009) The disease-protective complement factor H allotypic variant Ile62 shows increased binding affinity for C3b and enhanced cofactor activity. Hum Mol Genet 18:3452–3461CrossRefPubMedGoogle Scholar
  79. 79.
    Scharfstein J, Ferreira A, Gigli I, Nussenzweig V (1978) Human C4-binding protein. I. Isolation and characterization. J Exp Med 148:207–222CrossRefPubMedGoogle Scholar
  80. 80.
    Fujita T, Gigli I, Nussenzweig V (1978) Human C4-binding protein. II. Role in proteolysis of C4b by C3b-inactivator. J Exp Med 148:1044–1051CrossRefPubMedGoogle Scholar
  81. 81.
    Martinez-Barricarte R, Goicoechea de Jorge E, Montes T, Layana AG, Rodriguez de Cordoba S (2009) Lack of association between polymorphisms in C4b-binding protein and atypical haemolytic uraemic syndrome in the Spanish population. Clin Exp Immunol 155:59–64CrossRefPubMedGoogle Scholar
  82. 82.
    Kavanagh D, Goodship TH, Richards A (2006) Atypical haemolytic uraemic syndrome. Br Med Bull 77–78:5–22CrossRefPubMedGoogle Scholar
  83. 83.
    Loirat C, Fremeaux-Bacchi V (2008) Hemolytic uremic syndrome recurrence after renal transplantation. Pediatr Transplant 12:619–629CrossRefPubMedGoogle Scholar
  84. 84.
    Kavanagh D, Richards A, Goodship TH, Jalanko H (2010) Transplantation in atypical hemolytic uremic syndrome. Semin Thromb Hemost. doiGoogle Scholar
  85. 85.
    Bresin E, Daina E, Noris M, Castelletti F, Stefanov R, Hill P, Goodship TH, Remuzzi G (2006) Outcome of renal transplantation in patients with non-Shiga toxin-associated hemolytic uremic syndrome: prognostic significance of genetic background. Clin J Am Soc Nephrol 1:88–99CrossRefPubMedGoogle Scholar
  86. 86.
    Lehtinen MJ, Rops AL, Isenman DE, van der Vlag J, Jokiranta TS (2009) Mutations of factor H impair regulation of surface-bound C3b by three mechanisms in atypical hemolytic uremic syndrome. J Biol Chem 284:15650–15658CrossRefPubMedGoogle Scholar
  87. 87.
    Jozsi M, Heinen S, Hartmann A, Ostrowicz CW, Halbich S, Richter H, Kunert A, Licht C, Saunders RE, Perkins SJ, Zipfel PF, Skerka C (2006) Factor H and atypical hemolytic uremic syndrome: mutations in the C-terminus cause structural changes and defective recognition functions. J Am Soc Nephrol 17:170–177CrossRefPubMedGoogle Scholar
  88. 88.
    Jokiranta TS, Cheng ZZ, Seeberger H, Jozsi M, Heinen S, Noris M, Remuzzi G, Ormsby R, Gordon DL, Meri S, Hellwage J, Zipfel PF (2005) Binding of complement factor H to endothelial cells is mediated by the carboxy-terminal glycosaminoglycan binding site. Am J Pathol 167:1173–1181PubMedGoogle Scholar
  89. 89.
    Manuelian T, Hellwage J, Meri S, Caprioli J, Noris M, Heinen S, Jozsi M, Neumann HP, Remuzzi G, Zipfel PF (2003) Mutations in factor H reduce binding affinity to C3b and heparin and surface attachment to endothelial cells in hemolytic uremic syndrome. J Clin Invest 111:1181–1190PubMedGoogle Scholar
  90. 90.
    Sanchez-Corral P, Perez-Caballero D, Huarte O, Simckes AM, Goicoechea E, Lopez-Trascasa M, de Cordoba SR (2002) Structural and functional characterization of factor H mutations associated with atypical hemolytic uremic syndrome. Am J Hum Genet 71:1285–1295CrossRefPubMedGoogle Scholar

Copyright information

© IPNA 2010

Authors and Affiliations

  1. 1.The Institute of Human GeneticsNewcastle UniversityNewcastle upon TyneUK
  2. 2.Institute of Human GeneticsInternational Centre for LifeNewcastle upon TyneUK

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