A common single nucleotide polymorphism in the factor H gene predisposes to age-related macular degeneration. Factor H blocks the alternative pathway of complement on self-surfaces bearing specific polyanions, including the glycosaminoglycan chains of proteoglycans. Factor H also binds C-reactive protein, potentially contributing to noninflammatory apoptotic processes. The at risk sequence contains His (rather than Tyr) at position 402 (384 in the mature protein), in the seventh of the 20 complement control protein (CCP) modules (CCP7) of factor H. We expressed both His(402) and Tyr(402) variants of CCP7, CCP7,8, and CCP6-8. We determined structures of His(402) and Tyr(402) CCP7 and showed them to be nearly identical. The side chains of His/Tyr(402) have similar, solvent-exposed orientations far from interfaces with CCP6 and -8. Tyr(402) CCP7 bound significantly more tightly than His(402) CCP7 to a heparin affinity column as well as to defined-length sulfated heparin oligosaccharides employed in gel mobility shift assays. This observation is consistent with the position of the 402 side chain on the edge of one of two glycosaminoglycan-binding surface patches on CCP7 that we inferred on the basis of chemical shift perturbation studies with a sulfated heparin tetrasaccharide. According to surface plasmon resonance measurements, Tyr(402) CCP6-8 binds significantly more tightly than His(402) CCP6-8 to immobilized C-reactive protein. The data support a causal link between H402Y and age-related macular degeneration in which variation at position 402 modulates the response of factor H to age-related changes in the glycosaminoglycan composition and apoptotic activity of the macula.
"Around 30% of people of European descent carry at least one copy of the 402H risk allele (Sofat et al., 2012). Structurally, the Y402H polymorphism occurs in the seventh of FH's twenty complement control protein (CCP) domains (Fig. 2B) and does not alter the overall conformation of the protein (Herbert et al., 2007). Y402H, however, alters the binding of FH to a number of ligands (see Clark et al., 2010a and references within), most notably C-reactive protein (Sjöberg et al., 2007), Streptococcus M protein (Haapasalo et al., 2008) and sulfated polyanions (Clark et al., 2006), such as the glycosaminoglycan (GAG) chains of proteoglycans. "
[Show abstract][Hide abstract] ABSTRACT: Age-related macular degeneration (AMD) is a major cause of visual impairment in the western world. It is characterized by the presence of lipoproteinaceous deposits (drusen) in the inner layers of the retina. Immunohistochemistry studies identified deposition of complement proteins in the drusen as well as in the choroid. In the last decade, genetic studies have linked both common and rare variants in proteins of the complement system to increased risk of development of AMD. Here, we review the variants described to date and discuss the functional implications of dysregulation of the alternative pathway of complement in AMD.
"The direction of SNP effects on plasma CFH is shown for their minor alleles, and the same alleles are consistently associated with opposite effects on plasma CFHR1 concentration (Fig. 5A). In contrast, CFH SNPs that alter the sequence and potentially the function of the protein [rs1061170 encoding Y402H (20–22,35,36) and rs800292 encoding I62V (28,35,37)] have effects on plasma CFH that appear uncorrelated with their effects on AMD risk (Fig. 5). For example, the above two non-synonymous CFH SNPs are associated with either no effect or a marginally lower plasma CFH, whereas both show a substantially increased AMD risk. "
[Show abstract][Hide abstract] ABSTRACT: It is a longstanding puzzle why non-coding variants in the complement factor H (CFH) gene are more strongly associated with age-related macular degeneration (AMD) than functional coding variants that directly influence the alternative complement pathway. The situation is complicated by tight genetic associations across the region, including the adjacent CFH-related genes CFHR3 and CFHR1, which may themselves influence the alternative complement pathway and are contained within a common deletion (CNP147) which is associated with protection against AMD. It is unclear whether this association is mediated through a protective effect of low plasma CFHR1 concentrations, high plasma CFH or both. We examined the triangular relationships of CFH/CFHR3/CFHR1 genotype, plasma CFH or CFHR1 concentrations and AMD susceptibility in combined case-control (1,256 cases, 1,020 controls) and cross-sectional population (N=1,004) studies and carried out genome-wide association studies of plasma CFH and CFHR1 concentrations. A non-coding CFH SNP (rs6677604) and the CNP147 deletion were strongly correlated both with each other and with plasma CFH and CFHR1 concentrations. The plasma CFH-raising rs6677604 allele and raised plasma CFH concentration were each associated with AMD protection. In contrast, the protective association of the CNP147 deletion with AMD was not mediated by low plasma CFHR1, since AMD-free controls showed increased plasma CFHR1 compared with cases, but it may be mediated by the association of CNP147 with raised plasma CFH concentration. The results are most consistent with a regulatory locus within a 32 kb region of the CFH gene with a major effect on plasma CFH concentration and AMD susceptibility.
Human Molecular Genetics 07/2013; 22(23). DOI:10.1093/hmg/ddt336 · 6.39 Impact Factor
"The C-terminal SCRs in all CFHR proteins that correspond to SCR19 in factor H are highly conserved, while the most C-terminal SCRs which correspond to SCR20 in factor H (Fig. 2) are more diverse. SCR20 of factor H harbors an important heparin binding site (Herbert et al., 2007; Lehtinen et al., 2009), suggesting that the CFHRs may recognize and bind to different cell surfaces. The specific features of each CFHR protein are presented and discussed separately. "
[Show abstract][Hide abstract] ABSTRACT: Factor H related proteins comprise a group of five plasma proteins: CFHR1, CFHR2, CFHR3, CFHR4 and CFHR5, and each member of this group binds to the central complement component C3b. Mutations, genetic deletions, duplications or rearrangements in the individual CFHR genes are associated with a number of diseases including atypical hemolytic uremic syndrome (aHUS), C3 glomerulopathies (C3 glomerulonephritis (C3GN), dense deposit disease (DDD) and CFHR5 nephropathy), IgA nephropathy, age related macular degeneration (AMD) and systemic lupus erythematosus (SLE). Although complement regulatory functions were attributed to most of the members of the CFHR protein family, the precise role of each CFHR protein in complement activation and the exact contribution to disease pathology is still unclear. Recent publications show that CFHR proteins form homo- as well as heterodimers. Genetic abnormalities within the CFHR gene locus can result in hybrid proteins with affected dimerization or recognition domains which cause defective functions. Here we summarize the recent data about CFHR genes and proteins in order to better understand the role of CFHR proteins in complement activation and in complement associated diseases.
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