Abstract
The recent revolution in age-related macular degeneration (AMD) genetics has demonstrated that genetic alterations affecting the alternative pathway of the complement cascade have a major influence on AMD risk. One of the two most important genetic loci is on chromosome 1 and contains genes encoding complement factor H (FH) and the factor H related proteins (FHR proteins). In macular tissue, especially Bruch’s membrane, relatively high levels of a truncated splice variant of FH called factor H-like protein 1 (FHL-1) are present. Here we discuss how genetic variations may alter the amounts, or by altering their protein sequences, the functions of these proteins. In particular, the common Y402H polymorphism affects the ability of FHL-1 and FH to localize to Bruch’s membrane and the inner choroid because it alters the ability of these complement regulators to bind heparan sulphate (HS) in these structures. In addition, there is an age-related loss of HS from Bruch’s membrane. We hypothesize that a combination of poor binding of the 402H variants of FHL-1 and FH to Bruch’s membrane, combined with a decrease in binding due to age-related HS loss, eventually results in insufficient FHL-1 and FH binding to Bruch’s membrane. This could result in complement activation, inflammation and thereby predispose to AMD.
Highlights
Age-related macular degeneration (AMD) is a condition that results in destruction of the macula, which is the central part of the retina (Figure 1)
Cross section of the human eye highlights the macula; (B) In early age-related macular degeneration (AMD), extracellular deposits called drusen form within Bruch’s membrane underneath the retinal pigment epithelium (RPE); (C) Bruch’s membrane is composed of five layers: an elastin core is sandwiched between two collagenous layers and these are surrounded by basement membranes
Other coding variants in complement factor H (CFH) include a relatively common I62V polymorphism, which is contained within a protective haplotype; this may have functional consequences as it is within the binding site for C3b [27]
Summary
Age-related macular degeneration (AMD) is a condition that results in destruction of the macula, which is the central part of the retina (Figure 1). FH (and FHL-1) acts primarily on the alternative complement pathway It can disassociate factor B (FB; sometimes referred to as BbBa) from C3b on host surfaces thereby preventing the amplification of C3b deposition (see Figure 2C). The cleavage of FB bound to C3b creates an active C3 convertase capable of cleaving C3 into C3b; the C3 convertase is stabilized by the binding of factor P (FP, known as properdin) This is the start of the amplification loop of complement that leads to a rapid and uncontrolled deposition of C3b onto the surface (opsonisation), labeling it for uptake by phagocytosis, accompanied by the release of the potent anaphylatoxin, C3a. The identified alternative splice variant of FHR-4, known as FHR-4A, is shown it’s exact sequence and homology is still under investigation
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