Funktionelle Charakterisierung von Age-Related Maculopathy Susceptibility 2 - ARMS2
Age-related macular degeneration (AMD) is a heritable, progressive neurodegenerative disease and the leading cause of blindness in developed countries. AMD is characterized by the formation of drusen between the retinal pigment epithelium and Bruch's membrane. The progressive accumulation of drusen leads to the degeneration of photoreceptors and of pigmented epithelial cells. Beside age, genetic mutations represent the major risk factors for the development of AMD. Genome-wide linkage studies identified polymorphisms predominantly in complement genes such as CFH (Complement Factor H), CFB (Complement Factor B), C2, C3 and CFI (Complement Factor I )to be associated with AMD, indicating the major impact of innate immunity in disease development. Strongly associated with AMD is a polymorphism in a gene on chromosome 10q26, that was named ARMS2 (Age-Related Susceptibility Maculopathy 2) and which encodes a small protein with so far unclear functions. The ARMS2 risk variant includes the rs10490924 polymorphism, which leads to an alanine – serine exchange at amino acid position 69 (A69S). This polymorphism is in strong linkage disequilibrium with an InDel-mutation in the 3 'UTR, which contributes to ARMS2 mRNA instability. Both mutations are associated with an increased risk of AMD development in Caucasian and Japanese populations. An additional rs2736911 polymorphism, which results in a premature stop codon at protein position 38 (R38Stop) was described to be associated as a risk factor in the Chinese population.The present work describes for the first time the function of the ARMS2 protein. Recombinant ARMS2 binds to late apoptotic and necrotic cell surfaces, but not to native, living cells. Attached to surfaces, ARMS2 activates complement and increases C3b opsonization by the alternative pathway. Thereby surface attached ARMS2 recruits the complement activator properdin, which stabilizes C3 convertases and enhances C3b opsonization on the cell surface. Furthermore, ARMS2 expression is identified in human monocytes, as well as in microglia cells, the latter representing phagocytes in the retina. Thus low ARMS2 levels as caused by the ARMS2 risk haplotype likely reduce phagocytosis and clearance of dying cells in the retina. The ongoing accumulation of drusen and cell debris subsequently induces complement activation accompanied by a chronic inflammation. The results improve the understanding of AMD pathology and may help to develop a new complement-based therapy.