Semin Thromb Hemost 2010; 36(6): 641-652
DOI: 10.1055/s-0030-1262886
© Thieme Medical Publishers

Atypical Hemolytic Uremic Syndrome Associated with Mutations in Complement Regulator Genes

Moglie Le Quintrec1 , Lubka Roumenina2 , Marina Noris3 , Véronique Frémeaux-Bacchi2 , 4
  • 1Service de Néphrologie, Hôpital Foch, 40 rue Worth, Suresnes, Paris, France
  • 2Institut de recherche des Cordeliers, 15 rue de l'Ecole de Médecine, Paris, France
  • 3Transplant Research Center, Mario Negri Institute for Pharmacological Research, Ranica Bergamo, Italy
  • 4Assistance Publique des Hôpitaux de Paris, Service d'Immunologie Biologique, Hôpital Européen Georges Pompidou, 20 rue Leblanc, Paris, France
Further Information

Publication History

Publication Date:
23 September 2010 (online)

ABSTRACT

In the last 10 years the knowledge of the pathophysiology of atypical hemolytic uremic syndrome (aHUS) has substantially increased. Nevertheless, aHUS remains a severe disorder, in which early recognition of symptoms remains a key issue. The landmark discovery of genetic abnormalities in complement regulatory genes in most patients gave us new insights into the influence of each abnormality on the disease outcome and opened new perspectives for patient management. This allows a potentially more tailored approach in treating aHUS patients.

REFERENCES

  • 1 Sadler J E. Von Willebrand factor, ADAMTS13, and thrombotic thrombocytopenic purpura.  Blood. 2008;  112(1) 11-18
  • 2 Moake J L. Thrombotic microangiopathies.  N Engl J Med. 2002;  347(8) 589-600
  • 3 Tarr P I, Gordon C A, Chandler W L. Shiga-toxin-producing Escherichia coli and haemolytic uraemic syndrome.  Lancet. 2005;  365(9464) 1073-1086
  • 4 Copelovitch L, Kaplan B S. Streptococcus pneumoniae-associated hemolytic uremic syndrome.  Pediatr Nephrol. 2008;  23(11) 1951-1956
  • 5 Copelovitch L, Kaplan B S. The thrombotic microangiopathies.  Pediatr Nephrol. 2008;  23(10) 1761-1767
  • 6 Noris M, Remuzzi G. Atypical hemolytic-uremic syndrome.  N Engl J Med. 2009;  361(17) 1676-1687
  • 7 Walport M J. Complement. First of two parts.  N Engl J Med. 2001;  344(14) 1058-1066
  • 8 Zipfel P F, Skerka C. Complement regulators and inhibitory proteins.  Nat Rev Immunol. 2009;  9(10) 729-740
  • 9 Delvaeye M, Noris M, De Vriese A et al. Thrombomodulin mutations in atypical hemolytic-uremic syndrome.  N Engl J Med. 2009;  361(4) 345-357
  • 10 Pangburn M K. Cutting edge: localization of the host recognition functions of complement factor H at the carboxyl-terminal: implications for hemolytic uremic syndrome.  J Immunol. 2002;  169(9) 4702-4706
  • 11 Jokiranta T S, Jaakola V P, Lehtinen M J, Pärepalo M, Meri S, Goldman A. Structure of complement factor H carboxyl-terminus reveals molecular basis of atypical haemolytic uremic syndrome.  EMBO J. 2006;  25(8) 1784-1794
  • 12 Wu J, Wu Y Q, Ricklin D, Janssen B J, Lambris J D, Gros P. Structure of complement fragment C3b-factor H and implications for host protection by complement regulators.  Nat Immunol. 2009;  10(7) 728-733
  • 13 Heinen S, Hartmann A, Lauer N et al. Factor H-related protein 1 (CFHR-1) inhibits complement C5 convertase activity and terminal complex formation.  Blood. 2009;  114(12) 2439-2447
  • 14 Józsi M, Zipfel P F. Factor H family proteins and human diseases.  Trends Immunol. 2008;  29(8) 380-387
  • 15 Liszewski M K, Kemper C, Price J D, Atkinson J P. Emerging roles and new functions of CD46.  Springer Semin Immunopathol. 2005;  27(3) 345-358
  • 16 Nilsson S C, Nita I, Månsson L et al. Analysis of binding sites on complement factor I that are required for its activity.  J Biol Chem. 2010;  285(9) 6235-6245
  • 17 Cameron J S, Vick R. Letter: Plasma-C3 in haemolytic-uraemic syndrome and thrombotic thrombocytopenic purpura.  Lancet. 1973;  2(7835) 975
  • 18 Thompson R A, Winterborn M H. Hypocomplementaemia due to a genetic deficiency of beta 1H globulin.  Clin Exp Immunol. 1981;  46(1) 110-119
  • 19 Saunders R E, Abarrategui-Garrido C, Frémeaux-Bacchi V et al. The interactive factor H-atypical hemolytic uremic syndrome mutation database and website: update and integration of membrane cofactor protein and factor I mutations with structural models.  Hum Mutat. 2007;  28(3) 222-234
  • 20 Pickering M C, Cook H T. Translational mini-review series on complement factor H: renal diseases associated with complement factor H: novel insights from humans and animals.  Clin Exp Immunol. 2008;  151(2) 210-230
  • 21 Rougier N, Kazatchkine M D, Rougier J P et al. Human complement factor H deficiency associated with hemolytic uremic syndrome.  J Am Soc Nephrol. 1998;  9(12) 2318-2326
  • 22 Warwicker P, Goodship T H, Donne R L et al. Genetic studies into inherited and sporadic hemolytic uremic syndrome.  Kidney Int. 1998;  53(4) 836-844
  • 23 Caprioli J, Bettinaglio P, Zipfel P F Itaslian Registry of Familial and Recurrent HUS/TTP et al. The molecular basis of familial hemolytic uremic syndrome: mutation analysis of factor H gene reveals a hot spot in short consensus repeat 20.  J Am Soc Nephrol. 2001;  12(2) 297-307
  • 24 Ferreira V P, Herbert A P, Cortés C et al. The binding of factor H to a complex of physiological polyanions and C3b on cells is impaired in atypical hemolytic uremic syndrome.  J Immunol. 2009;  182(11) 7009-7018
  • 25 Venables J P, Strain L, Routledge D et al. Atypical haemolytic uraemic syndrome associated with a hybrid complement gene.  PLoS Med. 2006;  3(10) e431
  • 26 Dragon-Durey M A, Loirat C, Cloarec S et al. Anti-factor H autoantibodies associated with atypical hemolytic uremic syndrome.  J Am Soc Nephrol. 2005;  16(2) 555-563
  • 27 Józsi M, Strobel S, Dahse H M et al. Anti factor H autoantibodies block C-terminal recognition function of factor H in hemolytic uremic syndrome.  Blood. 2007;  110(5) 1516-1518
  • 28 Moore I, Strain L, Pappworth I et al. 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. 2010;  115(2) 379-387
  • 29 Richards A, Kemp E J, Liszewski M K et al. Mutations in human complement regulator, membrane cofactor protein (CD46), predispose to development of familial hemolytic uremic syndrome.  Proc Natl Acad Sci U S A. 2003;  100(22) 12966-12971
  • 30 Noris M, Brioschi S, Caprioli J International Registry of Recurrent and Familial HUS/TTP et al. Familial haemolytic uraemic syndrome and an MCP mutation.  Lancet. 2003;  362(9395) 1542-1547
  • 31 Freméaux-Bacchi V, Dragon-Durey M A, Blouin J et al. Complement factor I: a susceptibility gene for atypical haemolytic uraemic syndrome.  J Med Genet. 2004;  41(6) e84
  • 32 Bienaimé F, Dragon-Durey M A, Regnier C H et al. Mutations in components of complement influence the outcome of factor I-associated atypical hemolytic uremic syndrome.  Kidney Int. 2010;  77(4) 339-349
  • 33 Frémeaux-Bacchi V, Moulton E A, Kavanagh D et al. Genetic and functional analyses of membrane cofactor protein (CD46) mutations in atypical hemolytic uremic syndrome.  J Am Soc Nephrol. 2006;  17(7) 2017-2025
  • 34 Nilsson S C, Kalchishkova N, Trouw L A, Frémeaux-Bacchi V, Villoutreix B O, Blom A M. 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. 2010;  40(1) 172-185
  • 35 Fang C J, Frémeaux-Bacchi V, Liszewski M K et al. Membrane cofactor protein mutations in atypical hemolytic uremic syndrome (aHUS), fatal Stx-HUS, C3 glomerulonephritis, and the HELLP syndrome.  Blood. 2008;  111(2) 624-632
  • 36 Goicoechea de Jorge E, Harris C L, Esparza-Gordillo J et al. Gain-of-function mutations in complement factor B are associated with atypical hemolytic uremic syndrome.  Proc Natl Acad Sci U S A. 2007;  104(1) 240-245
  • 37 Roumenina L T, Jablonski M, Hue C et al. Hyperfunctional C3 convertase leads to complement deposition on endothelial cells and contributes to atypical hemolytic uremic syndrome.  Blood. 2009;  114(13) 2837-2845
  • 38 Frémeaux-Bacchi V, Miller E C, Liszewski M K et al. Mutations in complement C3 predispose to development of atypical hemolytic uremic syndrome.  Blood. 2008;  112(13) 4948-4952
  • 39 Furie B, Furie B C. Mechanisms of thrombus formation.  N Engl J Med. 2008;  359(9) 938-949
  • 40 Ståhl A L, Vaziri-Sani F, Heinen S et al. Factor H dysfunction in patients with atypical hemolytic uremic syndrome contributes to complement deposition on platelets and their activation.  Blood. 2008;  111(11) 5307-5315
  • 41 Licht C, Pluthero F G, Li L et al. Platelet-associated complement factor H in healthy persons and patients with atypical HUS.  Blood. 2009;  114(20) 4538-4545
  • 42 Pickering M C, de Jorge E G, Martinez-Barricarte R et al. Spontaneous hemolytic uremic syndrome triggered by complement factor H lacking surface recognition domains.  J Exp Med. 2007;  204(6) 1249-1256
  • 43 Caprioli J, Noris M, Brioschi S International Registry of Recurrent and Familial HUS/TTP et al. Genetics of HUS: the impact of MCP, CFH, and IF mutations on clinical presentation, response to treatment, and outcome.  Blood. 2006;  108(4) 1267-1279
  • 44 Dragon-Durey M A, Blanc C, Marliot F et al. The high frequency of complement factor H related CFHR1 gene deletion is restricted to specific subgroups of patients with atypical haemolytic uraemic syndrome.  J Med Genet. 2009;  46(7) 447-450
  • 45 Esparza-Gordillo J, Goicoechea de Jorge E, Buil A et al. 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. 2005;  14(5) 703-712
  • 46 Sullivan M, Erlic Z, Hoffmann M M et al. Epidemiological approach to identifying genetic predispositions for atypical hemolytic uremic syndrome.  Ann Hum Genet. 2010;  74(1) 17-26
  • 47 Esparza-Gordillo J, Jorge E G, Garrido C A et al. Insights into hemolytic uremic syndrome: segregation of three independent predisposition factors in a large, multiple affected pedigree.  Mol Immunol. 2006;  43(11) 1769-1775
  • 48 Frémeaux-Bacchi V, Kemp E J, Goodship J A et al. 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. 2005;  42 852-856
  • 49 Martínez-Barricarte R, Goicoechea de Jorge E, Montes T, Layana A G, Rodríguez de Córdoba S. Lack of association between polymorphisms in C4b-binding protein and atypical haemolytic uraemic syndrome in the Spanish population.  Clin Exp Immunol. 2009;  155(1) 59-64
  • 50 Blom A M, Bergström F, Edey M et al. 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. 2008;  180(9) 6385-6391
  • 51 Zipfel P F, Edey M, Heinen S et al. Deletion of complement factor H-related genes CFHR1 and CFHR3 is associated with atypical hemolytic uremic syndrome.  PLoS Genet. 2007;  3(3) e41
  • 52 Abarrategui-Garrido C, Martínez-Barricarte R, López-Trascasa M, de Córdoba S R, Sánchez-Corral P. Characterization of complement factor H-related (CFHR) proteins in plasma reveals novel genetic variations of CFHR1 associated with atypical hemolytic uremic syndrome.  Blood. 2009;  114(19) 4261-4271
  • 53 Sellier-Leclerc A L, Frémeaux-Bacchi V, Dragon-Durey M A French Society of Pediatric Nephrology et al. Differential impact of complement mutations on clinical characteristics in atypical hemolytic uremic syndrome.  J Am Soc Nephrol. 2007;  18(8) 2392-2400
  • 54 Neumann H P, Salzmann M, Bohnert-Iwan B et al. Haemolytic uraemic syndrome and mutations of the factor H gene: a registry-based study of German speaking countries.  J Med Genet. 2003;  40(9) 676-681
  • 55 Dragon-Durey M A, Frémeaux-Bacchi V, Loirat C et al. 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. 2004;  15(3) 787-795
  • 56 Geelen J, van den Dries K, Roos A et al. A missense mutation in factor I (IF) predisposes to atypical haemolytic uraemic syndrome.  Pediatr Nephrol. 2007;  22(3) 371-375
  • 57 Kavanagh D, Kemp E J, Mayland E et al. Mutations in complement factor I predispose to development of atypical hemolytic uremic syndrome.  J Am Soc Nephrol. 2005;  16(7) 2150-2155

Véronique Frémeaux-BacchiM.D. Ph.D. 

Service d'Immunologie Biologique, Hôpital Européen Georges Pompidou

20 rue Leblanc, 75 015 Paris, France

Email: veronique.fremeaux-bacchi@egp.aphp.fr