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

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 Noel, Catherine Sautes-Fridman, Lise Halbwachs-Mecarelli, John P Atkinson, Arnaud Lionet, Veronique Fremeaux-Bacchi

Research output: Contribution to journalArticle (Academic Journal)peer-review

89 Citations (Scopus)

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 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.

Translated title of the contributionA prevalent C3 mutation in aHUS patients causes a direct C3 convertase gain-of-function
Original languageEnglish
Pages (from-to)4182-91
Number of pages10
JournalBlood
Volume119
Issue number18
DOIs
Publication statusPublished - 3 May 2012

Keywords

  • Adolescent
  • Adult
  • Aged
  • Amino Acid Substitution
  • Antigens, CD46
  • Cells, Cultured
  • Child, Preschool
  • Complement C3
  • Complement Factor B
  • Disease Progression
  • Endothelial Cells
  • Endothelium, Vascular
  • Female
  • Haplotypes
  • Hemolytic-Uremic Syndrome
  • Humans
  • Infant
  • Kidney Failure, Chronic
  • Kidney Glomerulus
  • Male
  • Middle Aged
  • Models, Molecular
  • Mutation, Missense
  • Penetrance
  • Point Mutation
  • Protein Conformation
  • Surface Plasmon Resonance
  • Young Adult

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