TY - JOUR
T1 - A functional variant in the CFI gene confers a high risk of age-related macular degeneration
AU - Van De Ven, Johannes P.H.
AU - Nilsson, Sara C.
AU - Tan, Perciliz L.
AU - Buitendijk, Gabriëlle H.S.
AU - Ristau, Tina
AU - Mohlin, Frida C.
AU - Nabuurs, Sander B.
AU - Schoenmaker-Koller, Frederieke E.
AU - Smailhodzic, Dzenita
AU - Campochiaro, Peter A.
AU - Zack, Donald J.
AU - Duvvari, Maheswara R.
AU - Bakker, Bjorn
AU - Paun, Codrut C.
AU - Boon, Camiel J.F.
AU - Uitterlinden, Andre G.
AU - Liakopoulos, Sandra
AU - Klevering, B. Jeroen
AU - Fauser, Sascha
AU - Daha, Mohamed R.
AU - Katsanis, Nicholas
AU - Klaver, Caroline C.W.
AU - Blom, Anna M.
AU - Hoyng, Carel B.
AU - Den Hollander, Anneke I.
N1 - Funding Information:
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.).
PY - 2013/7
Y1 - 2013/7
N2 - Up to half of the heritability of age-related macular degeneration (AMD) is explained by common variants. 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.
AB - Up to half of the heritability of age-related macular degeneration (AMD) is explained by common variants. 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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U2 - 10.1038/ng.2640
DO - 10.1038/ng.2640
M3 - Article
C2 - 23685748
AN - SCOPUS:84879692071
SN - 1061-4036
VL - 45
SP - 813
EP - 817
JO - Nature Genetics
JF - Nature Genetics
IS - 7
ER -