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Maheswara Duvvari, Johannes van de Ven, Elena Volokhina, Nicole Saksens, Camiel Boon, Lies Hoefsloot, Lambert P. van den Heuvel, Carel Hoyng, Anneke Den Hollander; Novel CFH variants in patients with age-related macular degeneration. Invest. Ophthalmol. Vis. Sci. 2013;54(15):6176.
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Age-related macular degeneration (AMD) is associated with common variants in the complement factor H (CFH) gene. In addition, rare pathogenic CFH variants have been reported in AMD and in patients with basal laminar drusen (BLD), a clinical subtype of AMD. The goal of this study was to assess the frequency of CFH mutations in patients with BLD, and to validate their functional effect on the CFH protein.
We analyzed a panel of 156 probands who were diagnosed with BLD. All exon and intron-exon boundaries of the CFH gene were analyzed by Sanger sequencing. Prediction algorithms were used to predict the impact of missense changes on protein function. The frequency of identified variants was checked in public databases (1000 Genomes, ESP5400, dbSNP).
We identified 13 rare, heterozygous CFH variants in 15 (9.6%) patients, and three polymorphisms: Val62Ile in 35 (22.4%), His402Tyr in 124 (79.4%), and Glu936Asp in 32 (20.5%) patients. Seven variants (Leu3Val; Phe170Cys; Ala173Gly; Arg175Gln; Ser193Leu; Ile216Thr; Ala301AsnfsX25) are novel, three variants (Gln408X; Arg1078Ser; Arg1210Cys) were previously reported in AMD or BLD, and three variants (Gln400Lys; Gln950His; Thr956Met) were previously reported in atypical haemolytic uremic syndrome (aHUS). Six variants affect the N-terminal SCR domains (1-4) of CFH, which play a role in complement regulatory activity. Two variants affect the C-terminal SCR domains (18-20), which mediate surface binding and target recognition. Two variants affect SCR7 domain, necessary for binding heparin and CRP. One variant was found in SCR16 domain, the precise function is not known.
Rare CFH variants were detected in 9.6% of patients with the BLD subtype of AMD. Functional studies are in progress to assess the ligand binding and cofactor activity for all identified missense variations.
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