Aprevalent C3 mutation in aHUS patients causes a direct C3 convertase gain offunction

Lubka T. Roumenina, Marie Frimat, Elizabeth C. Miller, Francois Provot, Marie Agnes Dragon-Durey, Pauline Bordereau, Sylvain Bigot, Christophe Hue, Simon C. Satchell, Peter W. Mathieson, Christiane Mousson, Christian Noe, Catherine Sautes-Fridman, Lise Halbwachs-Mecarelli, John P. Atkinson, Arnaud Lionet, Veronique Fremeaux-Bacchi

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115 Scopus citations

Abstract

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 proinflammatory 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 R139WaHUS 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.

Original languageEnglish
Pages (from-to)4182-4191
Number of pages10
JournalBlood
Volume119
Issue number18
DOIs
StatePublished - May 3 2012

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