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A functional variant in the CFI gene confers a high risk of age-related macular degeneration

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Abstract

Up to half of the heritability of age-related macular degeneration (AMD) is explained by common variants1,2,3,4,5. Here, we report the identification of a rare, highly penetrant missense mutation in CFI encoding a p.Gly119Arg substitution that confers high risk of AMD (P = 3.79 × 10−6; odds ratio (OR) = 22.20, 95% confidence interval (CI) = 2.98–164.49). Plasma and sera from cases carrying the p.Gly119Arg substitution mediated the degradation of C3b, both in the fluid phase and on the cell surface, to a lesser extent than those from controls. Recombinant protein studies showed that the Gly119Arg mutant protein is both expressed and secreted at lower levels than wild-type protein. Consistent with these findings, human CFI mRNA encoding Arg119 had reduced activity compared to wild-type mRNA encoding Gly119 in regulating vessel thickness and branching in the zebrafish retina. Taken together, these findings demonstrate that rare, highly penetrant mutations contribute to the genetic burden of AMD.

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Figure 1: Haplotypes of SNPs surrounding the CFI gene in one case carrying the p.Gly188Ala variant (case 73) and three unrelated cases carrying the p.Gly119Arg variant (cases 8, 47, 69).
Figure 2: Schematic and structural view of the FI protein.
Figure 3: FI concentrations and degradation of C3b in plasma and serum.
Figure 4: Expression of recombinant FI in HEK293 cells and degradation of C3b and C4b by recombinant wild-type and mutant Gly119Arg FI.
Figure 5: In vivo analysis of the p.Gly119Arg variant.

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Acknowledgements

We thank B. Janssen, A. Brücker, T. Janssen-van Kempen and M. Verbiest for excellent technical assistance. This study was supported by the Netherlands Organization for Scientific Research (Vidi Innovational Research Award 016.096.309 to A.I.d.H.), the Foundation Fighting Blindness (grant C-GE-0811-0548-RAD04 to A.I.d.H.), the Swedish Research Council (K2012-66X-14928-09-5 to A.M.B.) and the Söderberg Foundation (to A.M.B.).

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J.P.H.v.d.V., S.C.N., P.L.T., S.B.N., N.K., A.M.B. and A.I.d.H. wrote the manuscript, and all authors approved and commented on it. J.P.H.v.d.V., G.H.S.B., T.R., D.S., P.A.C., D.J.Z., C.J.F.B., S.F., S.L., B.J.K., M.R. Duvvari, N.K., C.C.W.K. and C.B.H. recruited and evaluated subjects. J.P.H.v.d.V., P.L.T., F.E.S.-K., M.R. Daha, A.G.U., B.B. and C.C.P. performed the genetic analyses. S.C.N., F.C.M. and A.M.B. performed the functional FI assays. S.B.N. performed the structural analysis of the FI variants. P.L.T. and N.K. performed the in vivo analysis.

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Correspondence to Anneke I den Hollander.

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van de Ven, J., Nilsson, S., Tan, P. et al. A functional variant in the CFI gene confers a high risk of age-related macular degeneration. Nat Genet 45, 813–817 (2013). https://doi.org/10.1038/ng.2640

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