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J Med Genet 2004;41:e84 doi:10.1136/jmg.2004.019083
  • Online mutation report

Complement factor I: a susceptibility gene for atypical haemolytic uraemic syndrome

  1. V Fremeaux-Bacchi1,2,
  2. M-A Dragon-Durey1,
  3. J Blouin1,
  4. C Vigneau3,
  5. D Kuypers4,
  6. B Boudailliez5,
  7. C Loirat6,
  8. E Rondeau3,
  9. W H Fridman1,2
  1. 1Service d’Immunologie Biologique, Assistance Publique - Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Paris, France
  2. 2INSERM U255, Institut de recherche des Cordeliers, Paris, France
  3. 3Service de Néphrologie A, Hôpital Tenon, Paris, France
  4. 4Department of Nephrology and Renal Transplantation, University Hospitals, Leuven, Belgium
  5. 5Service de Pédiatrie, CHU d’Amiens, Amiens, France
  6. 6Service de Néphrologie, Hôpital Robert Debré, Paris
  1. Correspondence to:
 Dr V Frémeaux-Bacchi
 Service d’Immunologie Biologique, Hôpital Européen Georges Pompidou, 20–40 rue Leblanc, 75908 Paris cedex 15, France; veronique.fremeaux-bacchihop.egp.ap-hop-paris.fr
  • Received 3 February 2004
  • Accepted 5 March 2004

Haemolytic uraemic syndrome (HUS), the most frequent cause of acute renal failure in childhood, is characterised by the association of acute renal failure, microangiopathic haemolytic anaemia, and thrombocytopenia.1,2 The majority of HUS cases occur after an episode of infectious diarrhoea, and are associated with Escherichia coli O157:H7 infection. However, atypical cases of HUS occur in the absence of infectious diarrhoea, although less commonly. Some are inherited in either an autosomal dominant or a recessive pattern and these patients often experience relapse and progress to hypertension and chronic renal disease. Sporadic forms can occur with many of the same signs and symptoms. The pathophysiology of this syndrome is poorly understood. However, after the first association with a low antigenic level of C3 was identified, two complement alternative pathway proteins, factor H (FH) and recently membrane cofactor protein (CD46; MCP) have been identified as fostering the development of atypical HUS.3–7 The human complement cascade can be activated through three different pathways: the classical pathway, the lectin pathway, and the alternative pathway. Factor H and MCP are regulatory proteins of the alternative pathway.8 Since the description of a genetic association of the disease with the cluster of complement related genes on chromosome 1, several mutations have been reported on the exons coding for the C-terminal domains of FH, which are important for C3b binding.5,9–12 Recently, two groups presented evidence that CD46 mutations may also predispose to HUS.7,13 Considering the major role of FH in complement alternative pathway regulation, we speculated that other complement regulators might be involved in the disease process. Human complement factor I (factor I) is a serine proteinase that cleaves the α chain of C3b and plays a key role in inhibition of the alternative pathway amplification loop which generates …

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