title: Mapping rare, deleterious mutations in Factor H: Association with early onset, drusen burden, and lower antigenic levels in familial AMD.
abstract: The genetic architecture of age-related macular degeneration (AMD) involves numerous genetic variants, both common and rare, in the coding region of complement factor H (CFH). While these variants explain high disease burden in some families, they fail to explain the pathology in all. We selected families whose AMD was unexplained by known variants and performed whole exome sequencing to probe for other rare, highly penetrant variants. We identified four rare loss-of-function variants in CFH associated with AMD. Missense variant CFH 1:196646753 (C192F) segregated perfectly within a family characterized by advanced AMD and drusen temporal to the macula. Two families, each comprising a pair of affected siblings with extensive extramacular drusen, carried essential splice site variant CFH 1:196648924 (IVS6+1G>A) or missense variant rs139360826 (R175P). In a fourth family, missense variant rs121913058 (R127H) was associated with AMD. Most carriers had early onset bilateral advanced AMD and extramacular drusen. Carriers tended to have low serum Factor H levels, especially carriers of the splice variant. One missense variant (R127H) has been previously shown not to be secreted. The two other missense variants were produced recombinantly: compared to wild type, one (R175P) had no functional activity and the other (C192F) had decreased secretion.
authors: Ophthalmic Epidemiology and Genetics Service, New England Eye Center, Tufts Medical Center, Boston, MA 02111, USA.|Department of Ophthalmology, Tufts University School of Medicine, Boston, MA 02111, USA.
authors: Erin K
authors: EK
authors: Wagner
authors: Program in Medical and Population Genetics, Broad Institute, Cambridge, MA 02142, USA.|Partners HealthCare Center for Personalized Genetic Medicine, Boston, MA 02115, USA.|Division of Genetics, Brigham and Women's Hospital, Boston, MA 02115, USA.|Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, Boston, MA 02115, USA.|Faculty of Medical and Human Sciences, University of Manchester, Manchester M13 9PL, UK.
authors: Soumya
authors: S
authors: Raychaudhuri
authors: Ophthalmic Epidemiology and Genetics Service, New England Eye Center, Tufts Medical Center, Boston, MA 02111, USA.
authors: Mercedes B
authors: MB
authors: Villalonga
authors: Washington University School of Medicine, Department of Medicine, Division of Nephrology, Saint Louis, MO 63110, USA.
authors: Anuja
authors: A
authors: Java
authors: Washington University School of Medicine, Department of Medicine, Division of Rheumatology, Saint Louis, MO 63110, USA.
authors: Michael P
authors: MP
authors: Triebwasser
authors: Program in Medical and Population Genetics, Broad Institute, Cambridge, MA 02142, USA.|Partners HealthCare Center for Personalized Genetic Medicine, Boston, MA 02115, USA.|Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA 02114, USA.
authors: Mark J
authors: MJ
authors: Daly
authors: Washington University School of Medicine, Department of Medicine, Division of Rheumatology, Saint Louis, MO 63110, USA.
authors: John P
authors: JP
authors: Atkinson
authors: Ophthalmic Epidemiology and Genetics Service, New England Eye Center, Tufts Medical Center, Boston, MA 02111, USA.|Department of Ophthalmology, Tufts University School of Medicine, Boston, MA 02111, USA.|Sackler School of Graduate Biomedical Sciences, Tufts University, Boston, MA 02111, USA.
authors: Johanna M
authors: JM
authors: Seddon
mesh_terms: D019943:Amino Acid Substitution; D016570:Bruch Membrane / Q000473:pathology*; D002874:Chromosome Mapping; D017242:Complement Factor H / Q000235:genetics* / Q000378:metabolism; D015785:Eye Diseases, Hereditary / Q000097:blood / Q000235:genetics*; D005260:Female; D006801:Humans; D008268:Macular Degeneration / Q000097:blood / Q000235:genetics*; D008297:Male; D020125:Mutation, Missense; D010375:Pedigree; D015593:Retinal Drusen / Q000097:blood / Q000235:genetics*
chemical_list: D017242:Complement Factor H