FIGURE 10.

Hypothesis of the effects of FHR SVs on FH-complement regulation. (A) The hypothesis is that the FHR3₁₋₄-FHR4₉ fusion protein identified in a DDD patient (cluster 3) binds GAGs and C3b on glomerular cells, favouring the formation of an active AP C3 convertase that is resistant to FH-mediated decay, promoting the formation of highly electron-dense deposits in the glomerular basement membrane (GBM). (B) The FHR3-FHR1 fusion protein identified in a C3GN patient (cluster 4), through FHR1 portion, may generate multimeric complexes and through FHR3 domains increase the affinity of multimers for FH ligands and C3b, preventing FH-complement regulation (this process is known “FH deregulation”). The final effect is the bright C3 glomerular staining in the face of normal circulating C3. (C) In an IC-MPGN patient (cluster 2) we identified a heterozygous deletion of CFH-CFHR3-CFHR1. Low FH serum levels caused by the heterozygous deletion of the entire CFH gene may result in impaired FH-complement regulation both in the fluid phase and on the glomerular surface. The consequence is the deposition of C3b molecules on endothelial cells that promote glomerular chronic complement activation caused by immune-complexes.