Mutation in Complement Factor H and its Contribution to the Development of Age-Related Macular Degeneration

Jake Portillo

Introduction. Age related Macular Degeneration (AMD) is the leading cause of blindness in the United States, and affects upwards of 50 million individuals worldwide1,2. AMD is a complex disease with an etiology that is still not well understood. It is a disease of chronic inflammation in the eye, leading to damage of the retinal pigmented epithelium (RPE) and subsequent problems via processes like inadequate proteolysis, fatty deposits of drusen, and neovascularization in response to inflammatory factors such as VEGF2-4. Many cases of AMD are associated with genetic mutations, the most predominant one being a Y402H polymorphism in the Cfh gene. This mutation alters the activity of complement factor H (FH), a protective protein that prevents complement from attacking host cells5. Studies have shown that Cfh mutation predisposes towards exacerbated inflammatory response, and cripples the activity of Factor H-like protein 1 (FHL-1), a smaller protein with increased protective function within the eye5,6. Methods. In one study, fluorescent immunohistochemistry was used to observe the distribution of FH and FHL-1 in harvested human retinas, and chamber diffusion was used to study the permeability of Bruch’s membrane to FH and FHL-15. A second study used plate assays to look at the binding affinities of FH relative to FHL-1 and the effect of Y402H polymorphism on those affinities7. In another, 40 genetically identical female Cfh-/- mice were split into two 20-mouse colonies, each given identical food and lighting. After 9 months the mice were sacrificed, and their eyes were enucleated and prepared for various experiments. The harvested eyes were immunostained for various inflammatory markers and cytokines, as well as macrophages, to determine if there was an elevated response in either group6. Results. Both immunohistochemistry and chamber diffusion showed FHL-1 to have greater ability to pass Bruch’s membrane and enter all areas of the retina5. FHL-1 also showed increased binding affinity for various inflammatory factors relative to FH, and both had their affinities reduced by Y402H polymorphism7. Cfh -/- mice kept in a conventional environment showed markedly higher levels of inflammatory markers and macrophages relative to those kept in a specific pathogen free environment6. Conclusions. Studies show that FHL-1 plays a major role in protecting the RPE of the eye, and Y402H polymorphism is detrimental to its function. Y402H individuals are predisposed to more aggressive and difficult to treat forms of AMD due to these changes, and may require different forms of treatment than non-mutation-related AMD8.


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