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Maheswara R. Duvvari, Johannes P. H. van de Ven, Frederieke E. Schoenmaker-Koller, Carel B. Hoyng, Anneke I. Den Hollander; Complement Component-3 (C3) Gene Mutations in Patients with Basal Laminar Drusen, a Clinical Subtype of Age-Related Macular Degeneration. Invest. Ophthalmol. Vis. Sci. 2012;53(14):3310.
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Basal laminar drusen (BLD) is an early-onset subtype of age-related macular degeneration (AMD) characterized by innumerable, small hard drusen scattered throughout the retina. Polymorphisms in several components of the complement system have been associated with AMD, including polymorphisms in the complement factor H (CFH) gene (p.Y402H), and in the complement component-3 (C3) gene (p.R102G). Our group previously demonstrated that pathogenic mutations in the complement factor H (CFH) gene can cause BLD. Moreover, mutations in both the CFH and C3 genes are known to cause atypical hemolytic uremic syndrome (aHUS), characterized by progressive renal failure. We therefore hypothesized that mutations in the C3 gene may also be associated with BLD.
In this study we analyzed a panel of 96 probands who were clinically diagnosed as BLD upon fundus examination, fluorescein angiography, and optical coherence tomography. Renal function was tested by serum creatinine and urea levels. We designed primers to cover the complete open reading frame of the C3 gene, which comprises 41 exons. All exon and intron-exon boundaries were analyzed by direct DNA sequencing. All identified sequence variants were screened in 200 ethnically and age-matched control individuals who did not exhibit any signs of AMD.
Upon sequence analysis we identified three different heterozygous non-synonymous changes (p.K155Q, p.S1619R, and p.R735W) in a total of 7 patients. The p.K155Q variant was found in five patients and was also present in two of 200 healthy controls, suggesting that it is not pathogenic. The other two variants were each found in one patient, but not in 200 healthy controls. The p.S1619R variant was predicted not to be pathogenic using pathogenicity prediction programs (PolyPhen and SIFT). Interestingly, the p.R735W variant was predicted to be pathogenic and was previously shown to cause aHUS. However, the kidney function in this patient was normal. The patient’s fundus showed a pattern of a macular drusenoid pigment epithelium detachment surrounded by hard drusen and mid peripheral patches of chorioretinal atrophy. The typical pattern of BLD was displayed by fluorescein angiography.
Our results further support a role for rare pathogenic variants in the complement system in the pathogenesis of AMD. Further research is warranted to understand why certain individuals carrying C3 or CFH mutations develop BLD, while others develop aHUS.
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