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

van de Ven, Johannes P. H. ; Nilsson, Sara LU ; Tan, Perciliz L. ; Buitendijk, Gabrille H. S. ; Ristau, Tina ; Mohlin, Frida LU ; Nabuurs, Sander B. ; Schoenmaker-Koller, Frederieke E. ; Smailhodzic, Dzenita and Campochiaro, Peter A. , et al. (2013) In Nature Genetics 45(7). p.813-813
Abstract
Up to half of the heritability of age-related macular degeneration (AMD) is explained by common variants(1-5). 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 x 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... (More)
Up to half of the heritability of age-related macular degeneration (AMD) is explained by common variants(1-5). 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 x 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. (Less)
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Nature Genetics
volume
45
issue
7
pages
813 - 813
publisher
Nature Publishing Group
external identifiers
  • wos:000321005200018
  • scopus:84879692071
  • pmid:23685748
ISSN
1546-1718
DOI
10.1038/ng.2640
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English
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yes
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6e8c298e-6eea-4f8e-93ed-84b24934cf8b (old id 3975994)
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@article{6e8c298e-6eea-4f8e-93ed-84b24934cf8b,
  abstract     = {Up to half of the heritability of age-related macular degeneration (AMD) is explained by common variants(1-5). 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 x 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.},
  author       = {van de Ven, Johannes P. H. and Nilsson, Sara and Tan, Perciliz L. and Buitendijk, Gabrille H. S. and Ristau, Tina and Mohlin, Frida and Nabuurs, Sander B. and Schoenmaker-Koller, Frederieke E. and Smailhodzic, Dzenita and Campochiaro, Peter A. and Zack, Donald J. and Duvvari, Maheswara R. and Bakker, Bjorn and Paun, Codrut C. and Boon, Camiel J. F. and Uitterlinden, Andre G. and Liakopoulos, Sandra and Klevering, B. Jeroen and Fauser, Sascha and Daha, Mohamed R. and Katsanis, Nicholas and Klaver, Caroline C. W. and Blom, Anna and Hoyng, Carel B. and den Hollander, Anneke I.},
  issn         = {1546-1718},
  language     = {eng},
  number       = {7},
  pages        = {813--813},
  publisher    = {Nature Publishing Group},
  series       = {Nature Genetics},
  title        = {A functional variant in the CFI gene confers a high risk of age-related macular degeneration},
  url          = {http://dx.doi.org/10.1038/ng.2640},
  doi          = {10.1038/ng.2640},
  volume       = {45},
  year         = {2013},
}