Functional analyses of rare genetic variants in complement component C9 identified in patients with age-related macular degeneration
| Autor: | Mariann Kremlitzka, Eiko K. de Jong, Maartje J. Geerlings, Bjorn Bakker, Anneke I. den Hollander, Sarah de Jong, Carel B. Hoyng, Anna M. Blom, Sascha Fauser, Sara C. Nilsson |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Erythrocytes Mutant Biology Hemolysis Polymorphism Single Nucleotide Sensory disorders Donders Center for Medical Neuroscience [Radboudumc 12] Polymerization Macular Degeneration 03 medical and health sciences All institutes and research themes of the Radboud University Medical Center Polymorphism (computer science) Genetics medicine Animals Humans Molecular Biology Gene Genetics (clinical) Sheep HEK 293 cells Genetic Variation General Medicine Macular degeneration Complement C9 medicine.disease Molecular biology Recombinant Proteins In vitro Complement system HEK293 Cells 030104 developmental biology Lytic cycle Case-Control Studies |
| Zdroj: | Human Molecular Genetics, 27, 15, pp. 2678-2688 Human Molecular Genetics, 27, 2678-2688 |
| ISSN: | 1460-2083 0964-6906 |
| Popis: | Age-related macular degeneration (AMD) is a progressive disease of the central retina and the leading cause of irreversible vision loss in the western world. The involvement of abnormal complement activation in AMD has been suggested by association of variants in genes encoding complement proteins with disease development. A low-frequency variant (p.P167S) in the complement component C9 (C9) gene was recently shown to be highly associated with AMD; however, its functional outcome remains largely unexplored. In this study, we reveal five novel rare genetic variants (p.M45L, p.F62S, p.G126R, p.T170I and p.A529T) in C9 in AMD patients, and evaluate their functional effects in vitro together with the previously identified (p.R118W and p.P167S) C9 variants. Our results demonstrate that the concentration of C9 is significantly elevated in patients' sera carrying the p.M45L, p.F62S, p.P167S and p.A529T variants compared with non-carrier controls. However, no difference can be observed in soluble terminal complement complex levels between the carrier and non-carrier groups. Comparing the polymerization of the C9 variants we reveal that the p.P167S mutant spontaneously aggregates, while the other mutant proteins (except for C9 p.A529T) fail to polymerize in the presence of zinc. Altered polymerization of the p.F62S and p.P167S proteins associated with decreased lysis of sheep erythrocytes and adult retinal pigment epithelial-19 cells by carriers' sera. Our data suggest that the analyzed C9 variants affect only the secretion and polymerization of C9, without influencing its classical lytic activity. Future studies need to be performed to understand the implications of the altered polymerization of C9 in AMD pathology. |
| Databáze: | OpenAIRE |
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