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. 2010 Sep 4;376(9743):794-801.
doi: 10.1016/S0140-6736(10)60670-8. Epub 2010 Aug 25.

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

Daniel P Gale  1 , Elena Goicoechea de Jorge, H Terence Cook, Rubén Martinez-Barricarte, Andreas Hadjisavvas, Adam G McLean, Charles D Pusey, Alkis Pierides, Kyriacos Kyriacou, Yiannis Athanasiou, Konstantinos Voskarides, Constantinos Deltas, Andrew Palmer, Véronique Frémeaux-Bacchi, Santiago Rodriguez de Cordoba, Patrick H Maxwell, Matthew C Pickering
Affiliations

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

Daniel P Gale et al. Lancet. .

Abstract

Background: Complement 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.

Methods: We 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.

Findings: Occurrence 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.

Interpretation: CFHR5 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.

Funding: UK Medical Research Council and Wellcome Trust.

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Figures

Figure 1
Figure 1
Pedigrees of two ostensibly unrelated families from the Troodos mountain region, Cyprus, showing haplotypes at region of maximum linkage on chromosome 1 Green boxes are haplotypes (HapMap coordinates 192344247 to 201027281).
Figure 2
Figure 2
Renal biopsy sample of patient V-4 from family 1 (A) Periodic acid-Schiff stain of glomerulus demonstrating mesangial hypercellularity (arrow). (B) Immunoperoxidase stain for C3 showing granular staining on the capillary wall. (C and D) Electron micrographs showing prominent mesangial electron-dense deposits (black arrow), subendothelial deposits (arrowheads), and occasional subepithelial deposits (white arrow).
Figure 3
Figure 3
Genome-wide single-nucleotide polymorphism-based analysis LOD=logarithm of the odds.
Figure 4
Figure 4
Multiplex ligation-dependent probe amplification analysis of CFH and CFHR genes using genomic DNA from five individuals from families 1 and 2
Figure 5
Figure 5
Southern blot of EcoR1-digested genomic DNA from two unrelated controls (C1 and C2) and five individuals from families 1 and 2, probed with exon 2 of CFHR5 Arrows show orientation of PCR primers. Numbered black rectangles are CFHR5 exons. Double-headed arrows are EcoR1 restriction fragments. Red triangle shows the duplicated region.
Figure 6
Figure 6
Diagnostic PCR test for CFHR512123-9 Arrowhead shows one 298 bp product in the wild-type allele and arrows shows the 222 bp product in the allele associated with CFHR5 internal duplication.
Figure 7
Figure 7
Western blot of serum with a polyclonal anti-CFHR5 antibody for detection of CFHR5 In affected patients there is a slower migrating band consistent with the predicted molecular weight of CFHR512123-9. Duplicated short consensus repeat domains are shown in green. *Initial aminoacid sequence in the duplicate SCR1 differs from the original SCR1, as described in the text.
Figure 8
Figure 8
Functional analysis of CFHR5 proteins (A) Western blot of bound and unbound CFHR5 to complement-lysed erythrocyte membranes. (B) Quantitative data from three experiments analysing binding to complement-lysed erythrocyte membranes.
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References

    1. Hageman GS, Anderson DH, Johnson LV. A common haplotype in the complement regulatory gene factor H (HF1/CFH) predisposes individuals to age-related macular degeneration. Proc Natl Acad Sci USA. 2005;102:7227–7232. - PMC - PubMed
    1. de Cordoba SR, de Jorge E Goicoechea. Translational mini-review series on complement factor H: genetics and disease associations of human complement factor H. Clin Exp Immunol. 2008;151:1–13. - PMC - PubMed
    1. de Jorge E Goicoechea, Harris CL, Esparza-Gordillo J. Gain-of-function mutations in complement factor B are associated with atypical hemolytic uremic syndrome. Proc Natl Acad Sci USA. 2007;104:240–245. - PMC - PubMed
    1. Fremeaux-Bacchi V, Miller EC, Liszewski MK. Mutations in complement C3 predispose to development of atypical hemolytic uremic syndrome. Blood. 2008;112:4948–4952. - PMC - PubMed
    1. Pickering MC, Cook HT. Translational mini-review series on complement factor H: renal diseases associated with complement factor H: novel insights from humans and animals. Clin Exp Immunol. 2008;151:210–230. - PMC - PubMed

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