The disease-protective complement factor H allotypic variant Ile62 shows increased binding affinity for C3b and enhanced cofactor activity

Abstract

Mutations and polymorphisms in the gene encoding factor H (CFH) have been associated with atypical haemolytic uraemic syndrome, dense deposit disease and age-related macular degeneration. The disease-predisposing CFH variants show a differential association with pathology that has been very useful to unravel critical events in the pathogenesis of one or other disease. In contrast, the factor H (fH)-Ile(62) polymorphism confers strong protection to all three diseases. Using ELISA-based methods and surface plasmon resonance analyses, we show here that the protective fH-Ile(62) variant binds more efficiently to C3b than fH-Val(62) and competes better with factor B in proconvertase formation. Functional analyses demonstrate an increased cofactor activity for fH-Ile(62) in the factor I-mediated cleavage of fluid phase and surface-bound C3b; however, the two fH variants show no differences in decay accelerating activity. From these data, we conclude that the protective effect of the fH-Ile(62) variant is due to its better capacity to bind C3b, inhibit proconvertase formation and catalyze inactivation of fluid-phase and surface-bound C3b. This demonstration of the functional consequences of the fH-Ile(62) polymorphism provides relevant insights into the complement regulatory activities of fH that will be useful in disease prediction and future development of effective therapeutics for disorders caused by complement dysregulation.

ThePlasmodium falciparumblood stages acquire factor H family proteins to evade destruction by human complement

“…This exchange results in inappropriate ACP regulation in the retina, ultimately leading to the formation of drusen and vision loss (Skerka et al , 2007; reviewed in Skerka and Zipfel, 2008; Zipfel et al , 2010). Another FH polymorphism associated with AMD is the substitution of isoleucine with valine at position 62 [I(62)V], which results in and increased binding affinity for C3b and enhanced cofactor activity (Tortajada et al , 2009). …”

The role of the alternative pathway of complement activation in glomerular diseases

“…Y402H polymorphism (rs1061170) is defined by T-to-C transition at amino acid position 402 (CRP and heparin binding site), resulting in the substitution of Tyr402 by His402 [12,34]. In case of V62I (rs800292), guanine (G) is changed to adenine (A), causing single amino acid change (valine to isoleucine transition) [34,63]. Both SNPs are reported to be associated with various diseases including C3G, SLE and AMD [50,[63][64][65][66][67][68].…”

“…In case of V62I (rs800292), guanine (G) is changed to adenine (A), causing single amino acid change (valine to isoleucine transition) [34,63]. Both SNPs are reported to be associated with various diseases including C3G, SLE and AMD [50,[63][64][65][66][67][68]. The genome-wide association studies (GWAS) suggest that cumulative, synergistic effect of some SNPs, mainly in C3 and CFH genes, rather than a single mutation, contribute to the glomerular disease [50,65].…”

“…1), the 3D model of C3 places the MG1 (C3S/F; rs2230199) and C3d region (CFH binding site) in a close proximity [14,47]. This implicates the possibility that the presence of many different risks variants of C3 and CFH [50] + (DDD) --c.C1775T/p.R592Q (rs121909583) [101] + --V619 M (rs146613648) [64] + --R1303H [64] + --R13200Q [64] + --C1518R [64] + --D1625H [64] + --ΔDG3923 [64] + (DDD) + -c.131_146del; p.Leu44Argfs*19 [73] - [12,34,62,65,68] + (DDD, C3GN) + (SLE) -V62I (rs800292) [34,[63][64][65] + (DDD) [75] + − − Duplication in CFHR1 gene [39] + − − CFHR3-1 hybrid gene [76] + --CFHR2-CFHR5 hybrid gene [40] + --CFHR5-CFHR2 hybrid gene [77] + − − CFHR1-5 hybrid gene [80] + − − rs16840639 [69] - [34] + (DDD) --−20T/C (rs9427662) [34] + (DDD) --IVS1 + 75T/A [34] + (DDD) --IVS2 + 58C/T [34] + (DDD) --in a single individual may have a more potent effect on AP regulation and may increase the risk of GN development.…”

“…Other specific allele variants in the CFH gene (V62I/rs800292, IVS 2-18insTT, A473A) and in the CFHR5 gene (P46S/rs12097550, −249T/C/rs9427661, −20T/C/rs9427662, IVS1 + 75T/A, IVS2 + 58C/T) are considered to be associated with DDD [34]. The 62I variant of rs800292 confers protection against C3G, aHUS, and AMD, as it has a stronger ability to C3b binding and thus enhances the CFH-dependent AP inhibition both in fluids and on the cell surfaces [63]. Conversely, the V62 variant allele of rs800292 is less efficient at inactivating C3b, and it is a susceptibility allele for C3G, aHUS and AMD [64].…”