Background Age-related macular degeneration (AMD) is the leading cause of
blindness in developed countries. The polymorphism rs10490924 in the ARMS2
gene is highly associated with AMD and linked to an indel mutation
(del443ins54), the latter inducing mRNA instability. At present, the function
of the ARMS2 protein, the exact cellular sources in the retina and the
biological consequences of the rs10490924 polymorphism are unclear. Methods
Recombinant ARMS2 was expressed in Pichia pastoris, and protein functions were
studied regarding cell surface binding and complement activation in human
serum using fluoresence-activated cell sorting (FACS) as well as laser
scanning microscopy (LSM). Biolayer interferometry defined protein
interactions. Furthermore, endogenous ARMS2 gene expression was studied in
human blood derived monocytes and in human induced pluripotent stem cell-
derived microglia (iPSdM) by PCR and LSM. The ARMS2 protein was localized in
human genotyped retinal sections and in purified monocytes derived from AMD
patients without the ARMS2 risk variant by LSM. ARMS2 expression in monocytes
under oxidative stress was determined by Western blot analysis. Results Here,
we demonstrate for the first time that ARMS2 functions as surface complement
regulator. Recombinant ARMS2 binds to human apoptotic and necrotic cells and
initiates complement activation by recruiting the complement activator
properdin. ARMS2-properdin complexes augment C3b surface opsonization for
phagocytosis. We also demonstrate for the first time expression of ARMS2 in
human monocytes especially under oxidative stress and in microglia cells of
the human retina. The ARMS2 protein is absent in monocytes and also in
microglia cells, derived from patients homozygous for the ARMS2 AMD risk
variant (rs10490924). Conclusions ARMS2 is likely involved in complement-
mediated clearance of cellular debris. As AMD patients present with
accumulated proteins and lipids on Bruch’s membrane, ARMS2 protein deficiency
due to the genetic risk variant might be involved in drusen formation