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

Nature Genetics volume 45, pages 813–817 (2013)Cite this article

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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.).

Author information

Author notes

  1. Johannes P H van de Ven and Sara C Nilsson: These authors contributed equally to this work.

  2. Anna M Blom, Carel B Hoyng and Anneke I den Hollander: These authors jointly directed this work.

Authors and Affiliations

  1. Department of Ophthalmology, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands

    Johannes P H van de Ven, Frederieke E Schoenmaker-Koller, Dzenita Smailhodzic, Maheswara R Duvvari, Bjorn Bakker, Codrut C Paun, Camiel J F Boon, B Jeroen Klevering, Carel B Hoyng & Anneke I den Hollander

  2. Department of Laboratory Medicine Malmö, Section of Medical Protein Chemistry, Lund University, Malmö, Sweden

    Sara C Nilsson, Frida C Mohlin & Anna M Blom

  3. Center for Human Disease Modeling, Duke University, Durham, North Carolina, USA

    Perciliz L Tan & Nicholas Katsanis

  4. Department of Cell Biology, Duke University, Durham, North Carolina, USA

    Perciliz L Tan & Nicholas Katsanis

  5. Department of Pediatrics, Duke University, Durham, North Carolina, USA

    Perciliz L Tan & Nicholas Katsanis

  6. Department of Ophthalmology, Erasmus Medical Center, Rotterdam, The Netherlands

    Gabriëlle H S Buitendijk & Caroline C W Klaver

  7. Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands

    Gabriëlle H S Buitendijk, Andre G Uitterlinden & Caroline C W Klaver

  8. Department of Vitreoretinal Surgery, Center for Ophthalmology, University of Cologne, Cologne, Germany

    Tina Ristau, Sandra Liakopoulos & Sascha Fauser

  9. Center for Molecular and Biomolecular Informatics, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands

    Sander B Nabuurs

  10. Department of Ophthalmology, Johns Hopkins School of Medicine, Baltimore, Maryland, USA

    Peter A Campochiaro & Donald J Zack

  11. Department of Neuroscience, Johns Hopkins School of Medicine, Baltimore, Maryland, USA

    Peter A Campochiaro & Donald J Zack

  12. Genetic Laboratory of the Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands

    Andre G Uitterlinden

  13. Department of Nephrology, Leiden University Medical Center, Leiden, The Netherlands

    Mohamed R Daha

  14. Department of Human Genetics, Nijmegen Center for Molecular Life Sciences and Institute of Genetic and Metabolic Diseases, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands

    Anneke I den Hollander

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  1. Johannes P H van de Ven
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Contributions

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.

Corresponding author

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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