A functional variant in the CFI gene confers a high risk of age-related macular degeneration. A. den Hollander1,14, J. P. H. van de Ven1, S. C. Nilsson2, P. L. Tan3,4,5, G. H. S. Buitendijk6,7, T. Ristau8, F. C. Mohlin2, S. B. Nabuurs9, F. E. Schoenmaker-Koller1, D. Smailhodzic1, P. A. Campochiaro10,11, D. J. Zack10,11, M. R. Duvvari1, B. Bakker1, C. C. Paun1, C. J. F. Boon1, A. G. Uitterlinden7,12, S. Liakopoulos8, B. J. Klevering1, S. Fauser8, M. R. Daha13, N. Katsanis3,4,5, C. C. W. Klaver6,7, A. M. Blom2, C. B. Hoyng1 1) Dept Ophthalmology, Radboud Univ Nijmegen MC, Nijmegen, Netherlands; 2) Section of Medical Protein Chemistry, Dept Laboratory Medicine Malmö, Lund University, Malmö, Sweden; 3) Center for Human Disease Modeling, Duke University, Durham, NC; 4) Dept Cell Biology, Duke University, Durham, NC; 5) Dept Pediatrics, Duke University, Durham, NC; 6) Dept Ophthalmology, Erasmus MC, Rotterdam, the Netherlands; 7) Dept Epidemiology, Erasmus MC, Rotterdam, the Netherlands; 8) Center for Ophthalmology, University of Cologne, Cologne, Germany; 9) Center for Molecular and Biomolecular Informatics, Radboud Univ Nijmegen MC, Nijmegen, the Netherlands; 10) Dept Ophthalmology, Johns Hopkins School of Medicine, Baltimore, MD; 11) Dept Neuroscience, Johns Hopkins School of Medicine, Baltimore, MD; 12) Dept Internal Medicine, Erasmus MC, Rotterdam, the Netherlands; 13) Dept Nephrology, Leiden University MC, Leiden, the Netherlands; 14) Dept Human Genetics, Radboud University Nijmegen MC, Nijmegen, the Netherlands.

   Age-related macular degeneration (AMD) is the most common cause of blindness among the elderly. Genome-wide association studies have identified common variants in or near genes within the complement cascade, high-density lipoprotein cholesterol pathway, and extracellular matrix that are associated with AMD. Combined, these variants explain up to half of the heritability of AMD. To explore the role of rare, highly penetrant variants in AMD we focused on CFI, a gene that encodes Factor I, a serine protease that circulates in its inactive form and can inactivate all complement pathways by cleaving the chain of activated complement factors C3b and C4b. We identified a rare missense mutation, p.Gly119Arg, in 20 of 3,567 cases versus only one of 3,937 controls, consistent with p.Gly119Arg conferring a high risk for developing AMD (P= 3.79 x 10-6, odds ratio = 22.20; 95% confidence interval 2.98-164.49). The p.Gly119Arg mutation affects a highly conserved glycine residue in the CD5 domain of Factor I and is predicted to alter the packing and stability of this domain. The cases carrying the p.Gly119Arg variant had lower plasma Factor I levels compared to both controls and cases without a CFI variant. Plasma and serum samples of cases carrying the p.Gly119Arg substitution mediated the degradation of C3b both in the fluid phase and on the cell surface at a lower level compared to controls. Recombinant protein studies revealed that the p.Gly119Arg mutant protein is both expressed and secreted at lower levels than wildtype Factor I protein. Consistent with these findings, 119Arg-encoding human mRNA had reduced activity compared to 119Gly in regulating vessel thickness and branching in the zebrafish retina. This study provides the first direct evidence that Factor I deficiency confers a high risk of developing AMD. Taken together, these findings demonstrate that rare, highly penetrant mutations contribute to the genetic variance of AMD, with important implications for predictive testing and personalized treatment.

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