Atypical Hemolytic Uremic Syndrome Associated with Mutations in Complement Regulator Genes

 

 Buy Article Permissions and Reprints

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
  CrossrefPubMedGoogle Scholar
• 2 Moake J L. Thrombotic microangiopathies.  N Engl J Med. 2002;  347(8) 589-600
  CrossrefPubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 4 Copelovitch L, Kaplan B S. Streptococcus pneumoniae-associated hemolytic uremic syndrome.  Pediatr Nephrol. 2008;  23(11) 1951-1956
  CrossrefPubMedGoogle Scholar
• 5 Copelovitch L, Kaplan B S. The thrombotic microangiopathies.  Pediatr Nephrol. 2008;  23(10) 1761-1767
  CrossrefPubMedGoogle Scholar
• 6 Noris M, Remuzzi G. Atypical hemolytic-uremic syndrome.  N Engl J Med. 2009;  361(17) 1676-1687
  CrossrefPubMedGoogle Scholar
• 7 Walport M J. Complement. First of two parts.  N Engl J Med. 2001;  344(14) 1058-1066
  CrossrefPubMedGoogle Scholar
• 8 Zipfel P F, Skerka C. Complement regulators and inhibitory proteins.  Nat Rev Immunol. 2009;  9(10) 729-740
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 14 Józsi M, Zipfel P F. Factor H family proteins and human diseases.  Trends Immunol. 2008;  29(8) 380-387
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 17 Cameron J S, Vick R. Letter: Plasma-C3 in haemolytic-uraemic syndrome and thrombotic thrombocytopenic purpura.  Lancet. 1973;  2(7835) 975
  PubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 39 Furie B, Furie B C. Mechanisms of thrombus formation.  N Engl J Med. 2008;  359(9) 938-949
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar

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