A Hybrid CFHR3-1 Gene Causes Familial C3 Glomerulopathy

Abstract

Controlled activation of the complement system, a key component of innate immunity, enables destruction of pathogens with minimal damage to host tissue. Complement factor H (CFH), which inhibits complement activation, and five CFH-related proteins (CFHR1-5) compose a family of structurally related molecules. Combined deletion of CFHR3 and CFHR1 is common and confers a protective effect in IgA nephropathy. Here, we report an autosomal dominant complement-mediated GN associated with abnormal increases in copy number across the CFHR3 and CFHR1 loci. In addition to normal copies of these genes, affected individuals carry a unique hybrid CFHR3-1 gene. In addition to identifying an association between these genetic observations and complement-mediated kidney disease, these results provide insight into the protective role of the combined deletion of CFHR3 and CFHR1 in IgA nephropathy.

C3 Glomerulopathy

“…Five patients were previously described, comprising four patients with familial membranoproliferative GN (8) and one patient with persistent renal dysfunction and hypocomplementemia after streptococcal throat infection (13). No further familial cases were identified.…”

“…C3 glomerulopathy has been further divided into dense deposit disease (DDD) and C3 glomerulonephritis (C3GN) based on electron microscopy (EM) appearances. The underlying genetic defect has been identified in some hereditary forms of C3GN such as CFHR5 nephropathy (7,8). In contrast, most other reports of C3GN describe a diverse array of acquired and genetic abnormalities of complement regulation, in association with nonuniform histologic changes (6,9).…”

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

“…Single SLE cases associated with different C3 mutations have been reported in the Japanese population [73,74]. Further, first described in patients of Cypriot origin, familial cases of C3G, associated with mutant CFHR proteins, have also been found in patients of other ethnicities [39,40,[75][76][77][78].…”

“…The dysregulation of complement was present only on the certain surfaces, but (according to the authors) probably did not occur on the endothelium, explaining the C3G and not aHUS onset [39]. Malik et al [76] reported a unique hybrid CFHR3-1 gene, which caused a familial C3G. The authors speculate that this new gene interferes with C3 regulation by CFH and CFHR5, resulting in uncontrolled C3 activation and its accumulation in the kidney.…”

“…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.…”