Variations in the complement regulatory genes factor H (CFH) and factor H related 5 (CFHR5) are associated with membranoproliferative glomerulonephritis type II (dense deposit disease)

Abstract

Introduction: Membranoproliferative glomerulonephritis type II or dense deposit disease (MPGN II/DDD) causes chronic renal dysfunction that progresses to end stage renal disease in about half of patients within 10 years of diagnosis. Deficiency of and mutations in the complement factor H (CFH) gene are associated with the development of MPGN II/DDD, suggesting that dysregulation of the alternative pathway of the complement cascade is important in disease pathophysiology. Subjects: Patients with MPGN II/DDD were studied to determine whether specific allele variants of CFH and CFHR5 segregate preferentially with the MPGN II/DDD disease phenotype. The control group was compromised of 131 people in whom age related macular degeneration had been excluded. Results: Allele frequencies of four single nucleotide polymorphisms in CFH and three in CFHR5 were significantly different between MPGN II/DDD patients and controls. Conclusion: We have identified specific allele variants of CFH and CFHR5 associated with the MPGN II/ DDD disease phenotype. While our data can be interpreted to further implicate complement in the pathogenesis of MPGN II/DDD, these associations could also be unrelated to disease pathophysiology. Functional studies are required to resolve this question.

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

“…While CFHR3 and CFHR4 were revealed to possess a weak FI cofactor activity, CFHR5 bound C3b in vitro and exhibited both FI cofactor and decay acceleration activity. However, most of these AP-regulating activities of CFHRs are weak, and they were observed in in vitro assays, which used non-physiological CFHRs concentrations [23,24,31,32,[34][35][36].…”

“…The two common CFH SNPs, resulting in amino acid substitution and subsequent change of the protein function, are Y402H (rs1061170) and V62I (rs800292). 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].…”

“…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].…”

“…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.…”

“…The autoantibody against the C3 convertase termed C3 nephritic factor (C3NeF) is present in sera of 40% cases of C3GN and approximately 80% of DDD patients [34,62]. It has also been found in carriers of CFH mutations (about 54% of cases), as well as in healthy individuals [62,67].…”