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A prevalent C3 mutation in aHUS patients causes a direct C3 convertase gain of function.

Roumenina, Lubka T; Frimat, Marie; Miller, Elizabeth C; Provot, Francois; Dragon-Durey, Marie-Agnes; Bordereau, Pauline; Bigot, Sylvain; Hue, Christophe; Satchell, Simon C; Mathieson, Peter W; Mousson, Christiane; Noel, Christian; Sautes-Fridman, Catherine; Halbwachs-Mecarelli, Lise; Atkinson, John P; Lionet, Arnaud; Fremeaux-Bacchi, Veronique.
Blood; 119(18): 4182-91, 2012 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-22246034
Atypical hemolytic uremic syndrome (aHUS) is a rare renal thrombotic microangiopathy commonly associated with rare genetic variants in complement system genes, unique to each patient/family. Here, we report 14 sporadic aHUS patients carrying the same mutation, R139W, in the complement C3 gene. The clinical presentation was with a rapid progression to end-stage renal disease (6 of 14) and an unusually high frequency of cardiac (8 of 14) and/or neurologic (5 of 14) events. Although resting glomerular endothelial cells (GEnCs) remained unaffected by R139W-C3 sera, the incubation of those sera with GEnC preactivated with pro-inflammatory stimuli led to increased C3 deposition, C5a release, and procoagulant tissue-factor expression. This functional consequence of R139W-C3 resulted from the formation of a hyperactive C3 convertase. Mutant C3 showed an increased affinity for factor B and a reduced binding to membrane cofactor protein (MCP; CD46), but a normal regulation by factor H (FH). In addition, the frequency of at-risk FH and MCP haplotypes was significantly higher in the R139W-aHUS patients, compared with normal donors or to healthy carriers. These genetic background differences could explain the R139W-aHUS incomplete penetrance. These results demonstrate that this C3 mutation, especially when associated with an at-risk FH and/or MCP haplotypes, becomes pathogenic following an inflammatory endothelium-damaging event.
Selo DaSilva