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Abstract: TH-PO540

Association of a New Variant of Complement Regulator FHR2 with C3 Glomerulopathy

Session Information

Category: Glomerular Diseases

  • 1401 Glomerular Diseases: From Inflammation to Fibrosis

Authors

  • Zipfel, Peter F., Leibniz-Institut fur Naturstoff-Forschung und Infektionsbiologie eV Hans-Knoll-Institut, Jena, Thüringen, Germany
  • Perie, Luce, Leibniz-Institut fur Naturstoff-Forschung und Infektionsbiologie eV Hans-Knoll-Institut, Jena, Thüringen, Germany
  • Wiech, Thorsten, Universitatsklinikum Hamburg-Eppendorf, Hamburg, Hamburg, Germany
Background

C3 glomerulopathy (C3G) is caused by a dysregulation of the complement system leading to C3 deposition and formation of glomerular deposits. Several C3G patients harbor mutations or copy number variations in the human Factor H (FH) and/or Factor H-Related (FHRs) genes. Therefore, FH and FHRs are emerging immune targets for inhibition of the complement cascade, as well as markers to monitor patients on complement regulatory drugs to test their efficiency.

Methods

Here, we focused our study on FHR2, known to inhibit in vitro formation of the terminal complement complex. We identified new variants for the FHR2 gene in a cohort of C3G patients and performed detailed functional studies on the novel variant FHR2L46, which has the Pro at position 46 replaced by Leu. Patients with FHR2L46 variant presented increased FHR2 plasma level, as compared to controls and displayed FHR2 deposits in glomeruli. We generated a recombinant FHR2L46 mutant protein to gain insight into the effect of this novel FHR2 variant on complement regulation.

Results

As the amino acid exchange occurred in the first short consensus repeat (SCR1), we first tested if the Leu at position 46 altered FHR2 homodimerization and heterodimerization of FHR2 with FHR1 and FHR5. We observed that FHR2L46 binds significantly less to FHR2 and FHR1 but more to FHR5. Furthermore, FHR246L acquired the capacity to bind to cell surfaces by interacting with glycosaminoglycans heparin and malondialdehyde (MDA)-modified amino group (MAA) epitopes. FHR2L46 also bound substantially more to necrotic cells compared to wild-type FHR2 (FHR2WT). In contrast, no difference was observed between FHR2L46 and FHR2 WT binding to C3 and C5.

Conclusion

Taken together, the present study identified a novel FHR2L46 variant in a C3G patient and suggests that the FHR2L46 mutant forms stable oligomers with FHR5 and enhances complement activation.