title: A functional variant in the CFI gene confers a high risk of age-related macular degeneration.
abstract: 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.
authors.affiliation: Department of Ophthalmology, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands.
authors.forename: Johannes P H
authors.initials: JP
authors.lastname: van de Ven
authors.forename: Sara C
authors.initials: SC
authors.lastname: Nilsson
authors.forename: Perciliz L
authors.initials: PL
authors.lastname: Tan
authors.forename: Gabriëlle H S
authors.initials: GH
authors.lastname: Buitendijk
authors.forename: Tina
authors.initials: T
authors.lastname: Ristau
authors.forename: Frida C
authors.initials: FC
authors.lastname: Mohlin
authors.forename: Sander B
authors.initials: SB
authors.lastname: Nabuurs
authors.forename: Frederieke E
authors.initials: FE
authors.lastname: Schoenmaker-Koller
authors.forename: Dzenita
authors.initials: D
authors.lastname: Smailhodzic
authors.forename: Peter A
authors.initials: PA
authors.lastname: Campochiaro
authors.forename: Donald J
authors.initials: DJ
authors.lastname: Zack
authors.forename: Maheswara R
authors.initials: MR
authors.lastname: Duvvari
authors.forename: Bjorn
authors.initials: B
authors.lastname: Bakker
authors.forename: Codrut C
authors.initials: CC
authors.lastname: Paun
authors.forename: Camiel J F
authors.initials: CJ
authors.lastname: Boon
authors.forename: Andre G
authors.initials: AG
authors.lastname: Uitterlinden
authors.forename: Sandra
authors.initials: S
authors.lastname: Liakopoulos
authors.forename: B Jeroen
authors.initials: BJ
authors.lastname: Klevering
authors.forename: Sascha
authors.initials: S
authors.lastname: Fauser
authors.forename: Mohamed R
authors.initials: MR
authors.lastname: Daha
authors.forename: Nicholas
authors.initials: N
authors.lastname: Katsanis
authors.forename: Caroline C W
authors.initials: CC
authors.lastname: Klaver
authors.forename: Anna M
authors.initials: AM
authors.lastname: Blom
authors.forename: Carel B
authors.initials: CB
authors.lastname: Hoyng
authors.forename: Anneke I
authors.initials: AI
authors.lastname: den Hollander
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D030801:Animals, Genetically Modified; D001483:Base Sequence; D017244:Complement Factor I / Q000235:genetics* / Q000502:physiology; D004625:Embryo, Nonmammalian; D020022:Genetic Predisposition to Disease; D057809:HEK293 Cells; D006801:Humans; D008268:Macular Degeneration / Q000235:genetics* / Q000473:pathology; D008957:Models, Genetic; D008958:Models, Molecular; D020125:Mutation, Missense / Q000502:physiology; D012160:Retina / Q000196:embryology / Q000378:metabolism / Q000473:pathology; D012307:Risk Factors; D015027:Zebrafish
chemical_list: C493611:CFI protein, human; D017244:Complement Factor I