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. 2012 Jul;23(7):1155-60.
doi: 10.1681/ASN.2012020166. Epub 2012 May 24.

A hybrid CFHR3-1 gene causes familial C3 glomerulopathy

Talat H Malik  1 , Peter J Lavin, Elena Goicoechea de Jorge, Katherine A Vernon, Kirsten L Rose, Mitali P Patel, Marcel de Leeuw, John J Neary, Peter J Conlon, Michelle P Winn, Matthew C Pickering
Affiliations

A hybrid CFHR3-1 gene causes familial C3 glomerulopathy

Talat H Malik et al. J Am Soc Nephrol. 2012 Jul.

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.

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Figures

Figure 1.
Figure 1.
Pedigree with familial C3 glomerulopathy. Affected individuals indicate those with C3 glomerulopathy confirmed on renal biopsy. Probable affected indicates those with significant proteinuria (>300 mg/24 h or at least 3+ on urinalysis) or hematuria (at least 3+ on two occasions). Unaffected individuals are healthy and do not have abnormal urinalysis.
Figure 2.
Figure 2.
The CFHR3–1 hybrid gene structure, genomic breakpoint, and protein. (A) Schematic representation of the CFHR3–1 hybrid gene and protein. Red arrows indicate sites of probes giving three copy signals, whereas blue arrows depict probes giving two copy signals using copy number assays. Exons and protein domains are numbered. The intergenic distance between CFHR3 and CFHR1 is 24 kb. The genomic breakpoint (4959 bp into CFHR3 intron 3) was identified using paired-end mapping analysis of next-generation sequence and long-range genomic PCR and amplicon sequencing. The breakpoint sequence contained a CAG triplet not identified in the introns of either gene (red arrow). (B) Serum Western blot using polyclonal anti-CFH antibody demonstrated the presence of two additional protein bands of similar molecular mass only in sera from affected individuals. The two bands represent differentially glycosylated isoforms (designated α and β) comparable with that seen with CFHR1. CFHL-1, CFH-like protein 1, a protein derived from alternative splicing of the CFH gene that is visible on this gel only in the absence of CFHR1 protein (lane 2).
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References

    1. de Córdoba SR, de Jorge EG: Translational mini-review series on complement factor H: Genetics and disease associations of human complement factor H. Clin Exp Immunol 151: 1–13, 2008 - PMC - PubMed
    1. Davila S, Wright VJ, Khor CC, Sim KS, Binder A, Breunis WB, Inwald D, Nadel S, Betts H, Carrol ED, de Groot R, Hermans PW, Hazelzet J, Emonts M, Lim CC, Kuijpers TW, Martinon-Torres F, Salas A, Zenz W, Levin M, Hibberd ML, International Meningococcal Genetics Consortium : Genome-wide association study identifies variants in the CFH region associated with host susceptibility to meningococcal disease. Nat Genet 42: 772–776, 2010 - PubMed
    1. Fakhouri F, Frémeaux-Bacchi V, Noël LH, Cook HT, Pickering MC: C3 glomerulopathy: A new classification. Nat Rev Nephrol 6: 494–499, 2010 - PubMed
    1. Gharavi AG, Kiryluk K, Choi M, Li Y, Hou P, Xie J, Sanna-Cherchi S, Men CJ, Julian BA, Wyatt RJ, Novak J, He JC, Wang H, Lv J, Zhu L, Wang W, Wang Z, Yasuno K, Gunel M, Mane S, Umlauf S, Tikhonova I, Beerman I, Savoldi S, Magistroni R, Ghiggeri GM, Bodria M, Lugani F, Ravani P, Ponticelli C, Allegri L, Boscutti G, Frasca G, Amore A, Peruzzi L, Coppo R, Izzi C, Viola BF, Prati E, Salvadori M, Mignani R, Gesualdo L, Bertinetto F, Mesiano P, Amoroso A, Scolari F, Chen N, Zhang H, Lifton RP: Genome-wide association study identifies susceptibility loci for IgA nephropathy. Nat Genet 43: 321–327, 2011 - PMC - PubMed
    1. McRae JL, Duthy TG, Griggs KM, Ormsby RJ, Cowan PJ, Cromer BA, McKinstry WJ, Parker MW, Murphy BF, Gordon DL: Human factor H-related protein 5 has cofactor activity, inhibits C3 convertase activity, binds heparin and C-reactive protein, and associates with lipoprotein. J Immunol 174: 6250–6256, 2005 - PubMed

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