title: Age-related macular degeneration associated polymorphism rs10490924 in ARMS2 results in deficiency of a complement activator.
abstract: 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.
  
  
  
  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.
  
  
  
  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).
  
  
  
  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.
authors.affiliation: Department of Infection Biology, Leibniz Institute for Natural Product Research and Infection Biology, Beutenbergstrasse 11, 07745, Jena, Germany.
authors.forename: Sven
authors.initials: S
authors.lastname: Micklisch
authors.affiliation: Department of Infection Biology, Leibniz Institute for Natural Product Research and Infection Biology, Beutenbergstrasse 11, 07745, Jena, Germany.
authors.forename: Yuchen
authors.initials: Y
authors.lastname: Lin
authors.affiliation: Department of Ophthalmology, Charité Universitätsmedizin Berlin, Augustenburger Platz 1, 13353, Berlin, Germany.
authors.forename: Saskia
authors.initials: S
authors.lastname: Jacob
authors.affiliation: Laboratory for Experimental Immunology of the Eye, Department of Ophthalmology, University of Cologne, Joseph-Stelzmann-Str. 9, 50931, Cologne, Germany.
authors.forename: Marcus
authors.initials: M
authors.lastname: Karlstetter
authors.affiliation: Laboratory for Experimental Immunology of the Eye, Department of Ophthalmology, University of Cologne, Joseph-Stelzmann-Str. 9, 50931, Cologne, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Dannhausen
authors.affiliation: Department of Infection Biology, Leibniz Institute for Natural Product Research and Infection Biology, Beutenbergstrasse 11, 07745, Jena, Germany.
authors.forename: Prasad
authors.initials: P
authors.lastname: Dasari
authors.affiliation: Department of Infection Biology, Leibniz Institute for Natural Product Research and Infection Biology, Beutenbergstrasse 11, 07745, Jena, Germany.
authors.forename: Monika
authors.initials: M
authors.lastname: von der Heide
authors.affiliation: Department of Infection Biology, Leibniz Institute for Natural Product Research and Infection Biology, Beutenbergstrasse 11, 07745, Jena, Germany.
authors.forename: Hans-Martin
authors.initials: HM
authors.lastname: Dahse
authors.affiliation: Institute of Nutrition, Friedrich Schiller University Jena, Dornburger Str. 25, 07743, Jena, Germany.
authors.forename: Lisa
authors.initials: L
authors.lastname: Schmölz
authors.affiliation: Institute of Human Genetics, University of Regensburg, Franz-Josef-Strauß-Allee 11, 93053, Regensburg, Germany.
authors.forename: Felix
authors.initials: F
authors.lastname: Grassmann
authors.affiliation: Department of Infection Biology, Leibniz Institute for Natural Product Research and Infection Biology, Beutenbergstrasse 11, 07745, Jena, Germany.
authors.forename: Medhanie
authors.initials: M
authors.lastname: Alene
authors.affiliation: Laboratory for Experimental Immunology of the Eye, Department of Ophthalmology, University of Cologne, Joseph-Stelzmann-Str. 9, 50931, Cologne, Germany.
authors.forename: Sascha
authors.initials: S
authors.lastname: Fauser
authors.affiliation: Institute of Reconstructive Neurobiology, University of Bonn, Sigmund-Freud-Str. 25, 53127, Bonn, Germany.
authors.forename: Harald
authors.initials: H
authors.lastname: Neumann
authors.affiliation: Institute of Nutrition, Friedrich Schiller University Jena, Dornburger Str. 25, 07743, Jena, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Lorkowski
authors.affiliation: Department of Ophthalmology, University Hospital Regenburg, Franz-Josef-Strauß-Allee 11, 93053, Regensburg, Germany.
authors.forename: Diana
authors.initials: D
authors.lastname: Pauly
authors.affiliation: Institute of Human Genetics, University of Regensburg, Franz-Josef-Strauß-Allee 11, 93053, Regensburg, Germany.
authors.forename: Bernhard H
authors.initials: BH
authors.lastname: Weber
authors.affiliation: Department of Ophthalmology, Charité Universitätsmedizin Berlin, Augustenburger Platz 1, 13353, Berlin, Germany.
authors.forename: Antonia M
authors.initials: AM
authors.lastname: Joussen
authors.affiliation: Laboratory for Experimental Immunology of the Eye, Department of Ophthalmology, University of Cologne, Joseph-Stelzmann-Str. 9, 50931, Cologne, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Langmann
authors.affiliation: Department of Infection Biology, Leibniz Institute for Natural Product Research and Infection Biology, Beutenbergstrasse 11, 07745, Jena, Germany.|Friedrich Schiller University, Fürstengraben, 07743, Jena, Germany.
authors.forename: Peter F
authors.initials: PF
authors.lastname: Zipfel
authors.affiliation: Department of Infection Biology, Leibniz Institute for Natural Product Research and Infection Biology, Beutenbergstrasse 11, 07745, Jena, Germany. christine.skerka@hki-jena.de.
authors.forename: Christine
authors.identifier: 0000-0003-2374-6473
authors.initials: C
authors.lastname: Skerka
mesh_terms: D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D016466:CHO Cells; D003165:Complement System Proteins / Q000235:genetics / Q000378:metabolism*; D003412:Cricetulus; D005260:Female; D006497:Heparan Sulfate / Q000494:pharmacology; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007155:Immunologic Factors / Q000494:pharmacology; D008268:Macular Degeneration / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D008297:Male; D017628:Microglia / Q000187:drug effects / Q000378:metabolism; D008875:Middle Aged; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011414:Properdin / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects / Q000235:genetics; D011506:Proteins / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D012160:Retina / Q000378:metabolism / Q000473:pathology; D055815:Young Adult
chemical_list: D003165:Complement System Proteins; D006497:Heparan Sulfate; D006861:Hydrogen Peroxide; D007155:Immunologic Factors; D011414:Properdin; D011506:Proteins; C514392:ARMS2 protein, human