Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Pediatric Nephrology
Published in: Pediatric Nephrology 12/2010

01-12-2010 | Educational Review

Genetics and complement in atypical HUS

Authors: David Kavanagh, Tim Goodship

Published in: Pediatric Nephrology | Issue 12/2010

Login to get access

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.
Appendix
Available only for authorised users
Literature
1.
Kavanagh D, Richards A, Atkinson J (2008) Complement regulatory genes and hemolytic uremic syndromes. Annu Rev Med 59:293–309CrossRefPubMed
2.
Fogo A, Kashgarian M (2005) Diagnostic atlas of renal pathology. Elsevier Science, Amsterdam
3.
Tarr PI, Gordon CA, Chandler WL (2005) Shiga-toxin-producing Escherichia coli and haemolytic uraemic syndrome. Lancet 365:1073–1086PubMed
4.
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 24:687–696CrossRefPubMed
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 41:355–367CrossRefPubMed
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 96:141–177CrossRefPubMed
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 283:9475–9487CrossRefPubMed
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 181:2610–2619PubMed
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 53:836–844CrossRefPubMed
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 68:485–490CrossRefPubMed
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 15:787–795CrossRefPubMed
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 108:1267–1279CrossRefPubMed
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 40:676–681CrossRefPubMed
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 68:478–484CrossRefPubMed
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 PubMed
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 27:292–293CrossRefPubMed
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:e431CrossRefPubMed
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 182:7009–7018CrossRefPubMed
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 41:81–84CrossRefPubMed
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 52:171–180CrossRefPubMed
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 69:981–988CrossRefPubMed
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 111:5307–5315CrossRefPubMed
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 18:506–514CrossRefPubMed
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 375:891–900CrossRefPubMed
26.
Pangburn MK, Rawal N, Cortes C, Alam MN, Ferreira VP, Atkinson MA (2009) Polyanion-induced self-association of complement factor H. J Immunol 182:1061–1068PubMed
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 391:119–135CrossRefPubMed
28.
Richards A, Kavanagh D (2009) Pathogenesis of thrombotic microangiopathy: insights from animal models. Nephron Exp Nephrol 113:e97–e103CrossRefPubMed
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 31:424–428PubMed
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 161:2027–2034PubMed
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 204:1249–1256CrossRefPubMed
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 44:4100
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 44:111–122CrossRefPubMed
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 100:12966–12971CrossRefPubMed
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 17:2017–2025CrossRefPubMed
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 362:1542–1547CrossRefPubMed
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 74:17–26CrossRefPubMed
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 111:624–632CrossRefPubMed
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 146:257–270CrossRefPubMed
40.
Whaley K, Ruddy S (1976) Modulation of C3b hemolytic activity by a plasma protein distinct from C3b inactivator. Science 193:1011–1013CrossRefPubMed
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 14:749–756CrossRefPubMed
42.
Shiraishi S, Stroud RM (1975) Cleavage products of C4b produced by enzymes in human serum. Immunochemistry 12:935–939CrossRefPubMed
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 9:431–455CrossRefPubMed
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 156:1739–1754CrossRefPubMed
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 129:2051–2060PubMed
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 16:2150–2155CrossRefPubMed
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 45:95–105CrossRefPubMed
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:e84CrossRefPubMed
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 18:2392–2400CrossRefPubMed
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 77:339–349CrossRefPubMed
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 58:572–577CrossRefPubMed
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 40:172–185CrossRefPubMed
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 44:1835–1844CrossRefPubMed
54.
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 361:345–357CrossRefPubMed
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 104:240–245CrossRefPubMed
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 43:856–859CrossRefPubMed
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 114:2837–2845PubMed
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 4:1356–1362CrossRefPubMed
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 112:4948–4952CrossRefPubMed
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
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 114:4261–4271CrossRefPubMed
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 16:555–563CrossRefPubMed
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 111:1512–1514CrossRefPubMed
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 110:1516–1518CrossRefPubMed
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:e41CrossRefPubMed
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 46:2236–2243CrossRefPubMed
68.
Jenne DE, Tschopp J (1992) Clusterin: the intriguing guises of a widely expressed glycoprotein. Trends Biochem Sci 17:154–159CrossRefPubMed
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 82:118–125PubMed
70.
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 44:3162–3167CrossRefPubMed
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 44:1704–1708CrossRefPubMed
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 42:852–856CrossRefPubMed
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 14:703–712CrossRefPubMed
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 43:1769–1775CrossRefPubMed
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 19:639–646CrossRefPubMed
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 180:6385–6391PubMed
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 18:3452–3461CrossRefPubMed
79.
Scharfstein J, Ferreira A, Gigli I, Nussenzweig V (1978) Human C4-binding protein. I. Isolation and characterization. J Exp Med 148:207–222CrossRefPubMed
80.
Fujita T, Gigli I, Nussenzweig V (1978) Human C4-binding protein. II. Role in proteolysis of C4b by C3b-inactivator. J Exp Med 148:1044–1051CrossRefPubMed
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 155:59–64CrossRefPubMed
82.
Kavanagh D, Goodship TH, Richards A (2006) Atypical haemolytic uraemic syndrome. Br Med Bull 77–78:5–22CrossRefPubMed
83.
Loirat C, Fremeaux-Bacchi V (2008) Hemolytic uremic syndrome recurrence after renal transplantation. Pediatr Transplant 12:619–629CrossRefPubMed
84.
Kavanagh D, Richards A, Goodship TH, Jalanko H (2010) Transplantation in atypical hemolytic uremic syndrome. Semin Thromb Hemost. doi
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 1:88–99CrossRefPubMed
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 284:15650–15658CrossRefPubMed
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 17:170–177CrossRefPubMed
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 167:1173–1181PubMed
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 111:1181–1190PubMed
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 71:1285–1295CrossRefPubMed
Metadata
Title
Genetics and complement in atypical HUS
Authors
David Kavanagh
Tim Goodship
Publication date
01-12-2010
Publisher
Springer-Verlag
Published in
Pediatric Nephrology / Issue 12/2010
Print ISSN: 0931-041X
Electronic ISSN: 1432-198X
DOI
https://doi.org/10.1007/s00467-010-1555-5

Other articles of this Issue 12/2010

Pediatric Nephrology 12/2010 Go to the issue

Original Article

Mortality risk in children after renal allograft failure: a NAPRTCS study

Original Article

Plasma levels of acylated and total ghrelin in pediatric patients with chronic kidney disease

Review

Vitamin D deficiency and toxicity in chronic kidney disease: in search of the therapeutic window

Abstracts

44th Annual Meeting of the Japanese Society for Pediatric Nephrology, 26–27 June 2009, Tokyo, Japan

Original Article

Vitamin D insufficiency and effect of cholecalciferol in children with chronic kidney disease

Letter to the Editors

CD46-associated atypical hemolytic uremic syndrome with uncommon course caused by cblC deficiency