Sequence- and copy number variations in the human Factor H-CFHR gene cluster are linked to the kidney diseases, atypical Hemolytic Uremic Syndrome, C3 Glomerulopathy, Membranous Nephropathy, IgA Nephropathy and Systemic Lupus Erythematosus. Deletions or duplications generate mutant CFHR-genes resulting in the expression of FHR::FHR- and FHR::Factor H-hybrid-proteins and an altered FHR-, Factor H, plasma repertoire. This disease association shows an essential role of FHR proteins for glomerular integrity. FHRs are emerging complement and immune modulators: FHR1 is an inflammatory mediator and controls Factor H surface action whereas FHR2 blocks C3 convertase action and inhibits FHR1 mediated inflammation. FHR5 is a complement activator. FHRs together with Factor H, the central C3 convertase regulator, adjust complement activity in glomeruli. A clear association is emerging between genetic modifications and the various pathologic outcomes.

We aim to define how altered FHR variants cause pathology in the kidney, and evaluate whether FHR deposition in renal biopsies serve as diagnostic and predictive markers. We are interested to define role of FHR2 and FHR5 and evaluate how new FHR2 variants (not listed in the exome aggregation consortium database, ExAc) influence complement action, affect surface binding and complement regulation. Furthermore correlate FHR1-, FHR2- and FHR5 deposition with morphological changes, immunohistological staining or cellular modifications to define unique patterns for the various glomerular diseases, and aim to develop FHRs as diagnostic markers and coordinate with clinicians for individualized, complement targeting therapy.