The
factor H-related
protein family (CFHR) is a group of minor
plasma proteins genetically and structurally related to
complement factor H (fH). Notably, deficiency of CFHR1/CFHR3 associates with protection against
age-related macular degeneration and with the presence of anti-fH
autoantibodies in
atypical hemolytic uremic syndrome (aHUS). We have developed a proteomics strategy to analyze the CFHR
proteins in plasma samples from controls, patients with aHUS, and patients with type II
membranoproliferative glomerulonephritis. Here, we report on the identification of persons carrying novel deficiencies of CFHR1, CFHR3, and CFHR1/CFHR4A, resulting from point mutations in CFHR1 and CFHR3 or from a rearrangement involving CFHR1 and CFHR4. Remarkably, patients with aHUS lacking CFHR1, but not those lacking CFHR3, present anti-fH
autoantibodies, suggesting that generation of these
antibodies is specifically related to CFHR1 deficiency. We also report the characterization of a novel CFHR1 polymorphism, resulting from a gene conversion event between CFH and CFHR1, which strongly associates with aHUS. The risk allotype CFHR1*B, with greater sequence similarity to fH, may compete with fH, decreasing protection of cellular surfaces against
complement damage. In summary, our comprehensive analyses of the CFHR
proteins have improved our understanding of these
proteins and provided further insights into aHUS pathogenesis.