Identification of a mutation in complement factor H-related protein 5 in patients of Cypriot origin with glomerulonephritis

Abstract

SummaryBackgroundComplement is a key component of the innate immune system, and variation in genes that regulate its activation is associated with renal and other disease. We aimed to establish the genetic basis for a familial disorder of complement regulation associated with persistent microscopic haematuria, recurrent macroscopic haematuria, glomerulonephritis, and progressive renal failure.MethodsWe sought patients from the West London Renal and Transplant Centre (London, UK) with unusual renal disease and affected family members as a method of identification of new genetic causes of kidney disease. Two families of Cypriot origin were identified in which renal disease was consistent with autosomal dominant transmission and renal biopsy of at least one individual showed C3 glomerulonephritis. A mutation was identified via a genome-wide linkage study and candidate gene analysis. A PCR-based diagnostic test was then developed and used to screen for the mutation in population-based samples and in individuals and families with renal disease.FindingsOccurrence of familial renal disease cosegregated with the same mutation in the complement factor H-related protein 5 gene (CFHR5). In a cohort of 84 Cypriots with unexplained renal disease, four had mutation in CFHR5. Overall, we identified 26 individuals with the mutation and evidence of renal disease from 11 ostensibly unrelated kindreds, including the original two families. A mutant CFHR5 protein present in patient serum had reduced affinity for surface-bound complement. We term this renal disease CFHR5 nephropathy.InterpretationCFHR5 nephropathy accounts for a substantial burden of renal disease in patients of Cypriot origin and can be diagnosed with a specific molecular test. The high risk of progressive renal disease in carriers of the CFHR5 mutation implies that isolated microscopic haematuria or recurrent macroscopic haematuria should not be regarded as a benign finding in individuals of Cypriot descent.FundingUK Medical Research Council and Wellcome Trust.

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].…”

“…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.…”

“…All affected individuals had an internal duplication of exons 2 and 3 in CFHR5 gene, resulting in an expression of the mutant CFHR5 protein, with reduced affinity for the surface-bound complement. This new entity was called CFHR5 nephropathy, and it was classified as a subtype of C3G [7,75]. Other cases of C3G associated with mutant CFHR proteins have been described.…”

Challenges in Rare Variant Association Studies for Complex Kidney Traits: CFHR5 and IgA Nephropathy

“…18 In parallel, rare internal duplication within CFHR5 has been shown to cause a familial form of C3GN. 19 This disease, also known as CFHR5 nephropathy, is endemic to Cyprus, where the founder mutation likely arose in a common ancestor approximately 16 generations ago. The disease shares some clinical features of IgAN, including microscopic hematuria and synpharyngitic flares with characteristic episodes of macrohematuria.…”

Increasing evidence that genetic variation in Complement factor H related 5 (CFHR5) causes disease: A commentary on ‘Atypical haemolytic uremic syndrome and genetic aberrations in the complement factor-H-related 5 gene’

“…A duplication of two exons of the gene results in a C3 glomerulonephritis (CFHR5 nephropathy) in which there is deposition of complement in the kidneys and progressive renal failure without systemic complement depletion or thrombotic microangiopathy. 5 Dense deposit disease (membranoproliferative glomerulonephritis type II) is another C3 glomerulopathy caused by uncontrolled alternative pathway activation, and there is some evidence that single-nucleotide polymorphisms in CFHR5 may be associated with the condition. 6 Most recently, a child with persistent C3 glomerulopathy (histologically type I membranoproliferative glomerulonephritis) was found to be heterozygous for a single insertion causing a premature stop codon and reduced circulating CFHR5.…”