Novel C3 convertase gain of function in atypical haemolytic uraemic syndrome, caused by a frequent mutation in C3 (original) (raw)
2010, Molecular Immunology
C3 is a key component of the complement cascade, common to all three activation pathways. Mutations in C3 are related to a rare renal thrombotic microangiopatic disease -atypical haemolytic uraemic syndrome (aHUS). C3 sequencing of a large aHUS cohort (n = 282) led to the identification of 27 patients with C3 mutations, 12 of which carried the same mutation R139W, not found in healthy controls (n = 160). Most of the 12 patients come from the same geographic region and might have a common ancestor. In these patients the clinical outcome was unfavorable with 70% of patients progressing to end stage renal disease immediately or within the first years after the onset of the disease. Therefore it was important to find out whether and how this mutation is related to the disease pathogenesis. The R139 position in C3 is located in proximity to the FH SCR1-4 binding site. Accordingly, the R139W mutation resulted in weaker interaction with FH and MCP binding (studied by SPR and ELISA). In addition, real time monitoring of the C3-convertase formation demonstrated that the R139W-C3 formed a hyperactive convertase, depositing more C3 on the surface compared to the wild type. In order to understand how this mutation was related to the aHUS pathogenesis, endothelial cells models were applied. Adherent HUVEC and glomerular endothelial cells (GEnC) were incubated with normal sera (n = 40) or aHUS R139W patients sera (n = 3). Marked increase in C3 depositions was detected upon incubation of patients' sera in the case of TNFa/IFNg activated EC. The augmented C3 deposition was accompanied by increased C5a and sC5b-9 release and increased tissue factor (TF) expression on EC membrane. In conclusion, this is the first demonstration of a direct gain of function mutation in C3, leading to hyperactive C3 convertase. The abnormal R139W convertase deposited high amounts of C3 on EC and resulted in a pro-coagulant phenotype -a hallmark of aHUS.
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