title: Atypical haemolytic uraemic syndrome and mutations in complement regulator genes.
abstract: 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.
authors.affiliation: Service d'Immunologie Biologique, Hôpital Européen Georges Pompidou, AP-HP, 20 rue Leblanc, 75015, Paris, France.
authors.forename: Marie-Agnès
authors.initials: MA
authors.lastname: Dragon-Durey
authors.forename: Véronique
authors.initials: V
authors.lastname: Frémeaux-Bacchi
mesh_terms: D001323:Autoantibodies / Q000097:blood; D017242:Complement Factor H / Q000235:genetics; D017244:Complement Factor I / Q000235:genetics; D003165:Complement System Proteins / Q000235:genetics*; D006463:Hemolytic-Uremic Syndrome / Q000235:genetics* / Q000276:immunology*; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D051916:Membrane Cofactor Protein / Q000235:genetics; D018448:Models, Immunological; D009154:Mutation; D011697:Purpura, Thrombotic Thrombocytopenic / Q000235:genetics / Q000276:immunology
chemical_list: D001323:Autoantibodies; D051916:Membrane Cofactor Protein; D017242:Complement Factor H; D003165:Complement System Proteins; D017244:Complement Factor I