Springer Seminars in Immunopathology

, Volume 27, Issue 3, pp 359–374 | Cite as

Atypical haemolytic uraemic syndrome and mutations in complement regulator genes

  • Marie-Agnès Dragon-Durey
  • Véronique Frémeaux-BacchiEmail author
Original Article


Haemolytic uraemic syndrome (HUS) is a thrombotic microangiopathy (TMA) disorder characterised by the association of haemolytic anaemia, thrombocytopenia and acute renal failure. Atypical forms (non-related to shigatoxin) may be familial or sporadic, with frequent recurrences and most of them lead to end stage renal failure. During the last years, different groups have demonstrated genetic predisposition of atypical HUS involving complement components factor H (FH), CD46 [or membrane co-factor protein (MCP)] and factor I. These three proteins are involved in the regulation of the alternative pathway of the complement system. Several series have reported mutations in the FH gene (called HF1) in between 10 and 22% of atypical HUS patients. At this time, four pedigrees corresponding to 13 cases have been reported with an MCP mutation and four cases with a sporadic disease presented factor I mutation. Whereas FH mutations were reported in both familial and sporadic forms of HUS, CD46 mutations were restricted to familial HUS, and factor I mutations were only observed in cases of sporadic HUS. We speculate that the penetrance of the disease may be variable regarding the identified susceptibility factors. Recently, the analysis of single nucleotide polymorphisms in both HF1 and MCP in three large cohorts of HUS patients identified significant association between atypical HUS and HF1 and MCP particular alleles. All these results, together with the finding of anti-FH antibodies in some atypical HUS patients, strongly suggest that an abnormality in the regulation of the alternative pathway participates in the patho-physiological mechanisms of atypical HUS. The recent progress made in the determination of susceptibility factors for atypical HUS has permitted the development of new diagnostic tests and may eventually lead to new specific treatments to block the pathological process.


Thrombotic Thrombocytopenic Purpura Haemolytic Uraemic Syndrome Complement Control Protein Short Consensus Repeat Thrombotic Thrombocytopenic Purpura Patient 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. 1.
    Ault BH, Schmidt BZ, Fowler NL et al (1997) Human factor H deficiency. Mutations in framework cysteine residues and block in H protein secretion and intracellular catabolism. J Biol Chem 272(40):25168–25175CrossRefPubMedGoogle Scholar
  2. 2.
    Bogdanovic R, Cvoric A, Nikolic V et al (1988) Recurrent haemolytic–uraemic syndrome with hypocomplementaemia: a case report. Pediatr Nephrol 2(2):236–238CrossRefPubMedGoogle Scholar
  3. 3.
    Caprioli A, Pezzella C, Morelli R et al (1996) Enteropathogens associated with childhood diarrhea in Italy. The Italian Study Group on Gastrointestinal Infections. Pediatr Infect Dis J 15(10):876–883CrossRefPubMedGoogle Scholar
  4. 4.
    Caprioli J, Bettinaglio P, Zipfel PF et al (2001) 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 12(2):297–307PubMedGoogle Scholar
  5. 5.
    Coppo P, Bengoufa D, Veyradier A et al (2004) Prevalence and clinical significance of anti-nuclear autoantibodies in adult thrombotic microangiopathies. Medicine 83(4):233–244CrossRefPubMedGoogle Scholar
  6. 6.
    Dragon-Durey MA, Fremeaux-Bacchi V, Loirat C et al (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(3):787–795CrossRefPubMedGoogle Scholar
  7. 7.
    Dragon-Durey MA, Loirat C, Cloarec S et al (2005) Anti-Factor H autoantibodies associated with atypical hemolytic uremic syndrome. J Am Soc Nephrol 16(2):555–563CrossRefPubMedGoogle Scholar
  8. 8.
    Esparza-Gordillo J (2005) Predisposition to atypical hemolytic uremic syndrome involves the concurrence of different susceptibility alleles in the regulators of complement activation gene cluster in 1q32. Human Medical GeneticsGoogle Scholar
  9. 9.
    Filler G, Radhakrishnan S, Strain L et al (2004) Challenges in the management of infantile factor H associated hemolytic uremic syndrome. Pediatr NephrolGoogle Scholar
  10. 10.
    Fremeaux-Bacchi V, Dragon-Durey MA, Blouin J et al (2004) Complement factor I: a susceptibility gene for atypical haemolytic uraemic syndrome. J Med Genet 41(6):E84CrossRefPubMedGoogle Scholar
  11. 11.
    Fremeaux-Bacchi V, Kemp BE, Goodship J et al (2005) The development of atypical HUS is influenced by susceptibility factors in both Factor H and membrane cofactor protein—evidence from two independent cohorts. J Med Genet (in press)Google Scholar
  12. 12.
    Fujisaku A, Harley JB, Frank MB et al (1989) Genomic organization and polymorphisms of the human C3d/Epstein–Barr virus receptor. J Biol Chem 264(4):2118–2125PubMedGoogle Scholar
  13. 13.
    Hughes J, Nangaku M, Alpers CE et al (2000) C5b-9 membrane attack complex mediates endothelial cell apoptosis in experimental glomerulonephritis. Am J Physiol Renal Physiol 278(5):F747–F7457PubMedGoogle Scholar
  14. 14.
    Janatova J, Reid KB, Willis AC (1989) Disulfide bonds are localized within the short consensus repeat units of complement regulatory proteins: C4b-binding protein. Biochemistry 28(11):4754–4761CrossRefPubMedGoogle Scholar
  15. 15.
    Kohl J (2001) Anaphylatoxins and infectious and non-infectious inflammatory diseases. Mol Immunol 38(2–3):175–187CrossRefPubMedGoogle Scholar
  16. 16.
    Leitao MF, Vilela MM, Rutz R et al (1997) Complement factor I deficiency in a family with recurrent infections. Immunopharmacology 38(1–2):207–213CrossRefPubMedGoogle Scholar
  17. 17.
    Liszewski MK, Leung M, Cui W et al (2000) Dissecting sites important for complement regulatory activity in membrane cofactor protein (MCP; CD46). J Biol Chem 275(48):37692–37701CrossRefPubMedGoogle Scholar
  18. 18.
    Manuelian T, Hellwage J, Meri S et al (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(8):1181–1190CrossRefPubMedGoogle Scholar
  19. 19.
    Murphy B, Georgiou T, Machet D et al (2002) Factor H-related protein-5: a novel component of human glomerular immune deposits. Am J Kidney Dis 39(1):24–27CrossRefPubMedGoogle Scholar
  20. 20.
    Nangaku M, Alpers CE, Pippin J et al (1997) A new model of renal microvascular endothelial injury. Kidney Int 52(1):182–194PubMedCrossRefGoogle Scholar
  21. 21.
    Nangaku M, Alpers CE, Pippin J et al (1997) Renal microvascular injury induced by antibody to glomerular endothelial cells is mediated by C5b-9. Kidney Int 52(6):1570–1578PubMedCrossRefGoogle Scholar
  22. 22.
    Neumann HP, Salzmann M, Bohnert-Iwan B et al (2003) Haemolytic uraemic syndrome and mutations of the factor H gene: a registry-based study of German speaking countries. J Med Genet 40(9):676–681CrossRefPubMedGoogle Scholar
  23. 23.
    Noris M, Brioschi S, Caprioli J et al (2003) Familial haemolytic uraemic syndrome and an MCP mutation. Lancet 362(9395):1542–1547CrossRefPubMedGoogle Scholar
  24. 24.
    Pangburn MK (2002) Cutting edge: localization of the host recognition functions of complement factor H at the carboxyl-terminal: implications for hemolytic uremic syndrome. J Immunol 169(9):4702–4706PubMedGoogle Scholar
  25. 25.
    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(1):257–270CrossRefPubMedGoogle Scholar
  26. 26.
    Perez-Caballero D, Gonzalez-Rubio C, Gallardo ME et al (2001) Clustering of missense mutations in the C-terminal region of factor H in atypical hemolytic uremic syndrome. Am J Hum Genet 68(2):478–484CrossRefPubMedGoogle Scholar
  27. 27.
    Perkins SJ, Goodship TH (2002) Molecular modelling of the C-terminal domains of factor H of human complement: a correlation between haemolytic uraemic syndrome and a predicted heparin binding site. J Mol Biol 316(2):217–224CrossRefPubMedGoogle Scholar
  28. 28.
    Petermann A, Offermann G, Distler A et al (1998) Familial hemolytic–uremic syndrome in three generations. Am J Kidney Dis 32(6):1063–1067PubMedGoogle Scholar
  29. 29.
    Pichette V, Querin S, Schurch W et al (1994) Familial hemolytic–uremic syndrome and homozygous factor H deficiency. Am J Kidney Dis 24(6):936–941PubMedGoogle Scholar
  30. 30.
    Remuzzi G, Ruggenenti P, Codazzi D et al (2002) Combined kidney and liver transplantation for familial haemolytic uraemic syndrome. Lancet 359(9318):1671–1672CrossRefPubMedGoogle Scholar
  31. 31.
    Richards A, Buddles MR, Donne RL et al (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(2):485–490CrossRefPubMedGoogle Scholar
  32. 32.
    Richards A, Kemp EJ, Liszewski MK et al (2003) Mutations in human complement regulator, membrane cofactor protein (CD46), predispose to development of familial hemolytic uremic syndrome. Proc Natl Acad Sci U S A 100(22):12966–12971CrossRefPubMedGoogle Scholar
  33. 33.
    Riley-Vargas RC, Gill DB, Kemper C et al (2004) CD46: expanding beyond complement regulation. Trends Immunol 25(9):496–503CrossRefPubMedGoogle Scholar
  34. 34.
    Rodriguez de Cordoba S, Lublin DM, Rubinstein P et al (1985) Human genes for three complement components that regulate the activation of C3 are tightly linked. J Exp Med 161(5):1189–1195CrossRefPubMedGoogle Scholar
  35. 35.
    Rougier N, Kazatchkine MD, Rougier JP et al (1998) Human complement factor H deficiency associated with hemolytic uremic syndrome. J Am Soc Nephrol 9(12):2318–2326PubMedGoogle Scholar
  36. 36.
    Sanchez-Corral P, Perez-Caballero D, Huarte O et al (2002) Structural and functional characterization of factor H mutations associated with atypical hemolytic uremic syndrome. Am J Hum Genet 71(6):1285–1295CrossRefPubMedGoogle Scholar
  37. 37.
    Schmidt BZ, Fowler NL, Hidvegi T et al (1999) Disruption of disulfide bonds is responsible for impaired secretion in human complement factor H deficiency. J Biol Chem 274(17):11782–11788CrossRefPubMedGoogle Scholar
  38. 38.
    Schraufstatter IU, Trieu K, Sikora L et al (2002) Complement c3a and c5a induce different signal transduction cascades in endothelial cells. J Immunol 169(4):2102–2110PubMedGoogle Scholar
  39. 39.
    Tarr PI, Gordon CA, Chandler WL (2005) Shiga-toxin-producing Escherichia coli and haemolytic uraemic syndrome. Lancet 365(9464):1073–1086PubMedGoogle Scholar
  40. 40.
    Thompson RA, Winterborn MH (1981) Hypocomplementaemia due to a genetic deficiency of beta 1H globulin. Clin Exp Immunol 46(1):110–119PubMedGoogle Scholar
  41. 41.
    Vyse TJ, Spath PJ, Davies KA et al (1994) Hereditary complement factor I deficiency. Qjm 87(7):385–401PubMedGoogle Scholar
  42. 42.
    Warwicker P, Goodship TH, Donne RL et al (1998) Genetic studies into inherited and sporadic hemolytic uremic syndrome. Kidney Int 53(4):836–844CrossRefPubMedGoogle Scholar
  43. 43.
    Watanabe H, Kuraya M, Kasukawa R et al (1995) Analysis of C5a receptor by monoclonal antibody. J Immunol Methods 185(1):19–29CrossRefPubMedGoogle Scholar
  44. 44.
    Weis JH, Morton CC, Bruns GA et al (1987) A complement receptor locus: genes encoding C3b/C4b receptor and C3d/Epstein–Barr virus receptor map to 1q32. J Immunol 138(1):312–315PubMedGoogle Scholar
  45. 45.
    Wiedmer T, Sims PJ (1991) Participation of protein kinases in complement C5b-9-induced shedding of platelet plasma membrane vesicles. Blood 78(11):2880–2886PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2005

Authors and Affiliations

  • Marie-Agnès Dragon-Durey
    • 1
  • Véronique Frémeaux-Bacchi
    • 1
    • 2
    Email author
  1. 1.Service d'Immunologie BiologiqueHôpital Européen Georges PompidouParisFrance
  2. 2.INSERM U255Institut de recherche des CordeliersParisFrance

Personalised recommendations