The rare C9 P167S risk variant for age-related macular degeneration increases polymerization of the terminal component of the complement cascade.

Autor:	McMahon O; Complement Therapeutics Research Group, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK.; National Renal Complement Therapeutics Centre, Royal Victoria Infirmary, Newcastle upon Tyne, NE1 4LP, UK., Hallam TM; Complement Therapeutics Research Group, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK.; National Renal Complement Therapeutics Centre, Royal Victoria Infirmary, Newcastle upon Tyne, NE1 4LP, UK., Patel S; Department of Ophthalmology and Visual Sciences, University of Massachusetts Medical School, Worcester, MA 01655, USA., Harris CL; Complement Therapeutics Research Group, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK.; National Renal Complement Therapeutics Centre, Royal Victoria Infirmary, Newcastle upon Tyne, NE1 4LP, UK., Menny A; Department of Life Sciences, Sir Ernst Chain Building, Imperial College London, London SW7 2AZ, UK., Zelek WM; Division of Infection and Immunity, School of Medicine, Systems Immunity Research Institute, Cardiff University, Heath Park, Cardiff CF14 4XN, UK., Widjajahakim R; Department of Ophthalmology and Visual Sciences, University of Massachusetts Medical School, Worcester, MA 01655, USA., Java A; Divisions of Nephrology and Rheumatology, Department of Medicine, Washington University, St Louis, MO 63110, USA., Cox TE; Complement Therapeutics Research Group, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK.; National Renal Complement Therapeutics Centre, Royal Victoria Infirmary, Newcastle upon Tyne, NE1 4LP, UK., Tzoumas N; Biosciences Institute, Newcastle University, Newcastle upon Tyne, NE1 3BZ, UK., Steel DHW; Biosciences Institute, Newcastle University, Newcastle upon Tyne, NE1 3BZ, UK., Shuttleworth VG; Complement Therapeutics Research Group, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK.; National Renal Complement Therapeutics Centre, Royal Victoria Infirmary, Newcastle upon Tyne, NE1 4LP, UK., Smith-Jackson K; Complement Therapeutics Research Group, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK.; National Renal Complement Therapeutics Centre, Royal Victoria Infirmary, Newcastle upon Tyne, NE1 4LP, UK., Brocklebank V; Complement Therapeutics Research Group, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK.; National Renal Complement Therapeutics Centre, Royal Victoria Infirmary, Newcastle upon Tyne, NE1 4LP, UK., Griffiths H; Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton SO16 6YD, UK., Cree AJ; Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton SO16 6YD, UK., Atkinson JP; Divisions of Nephrology and Rheumatology, Department of Medicine, Washington University, St Louis, MO 63110, USA., Lotery AJ; Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton SO16 6YD, UK., Bubeck D; Department of Life Sciences, Sir Ernst Chain Building, Imperial College London, London SW7 2AZ, UK., Morgan BP; Division of Infection and Immunity, School of Medicine, Systems Immunity Research Institute, Cardiff University, Heath Park, Cardiff CF14 4XN, UK., Marchbank KJ; Complement Therapeutics Research Group, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK.; National Renal Complement Therapeutics Centre, Royal Victoria Infirmary, Newcastle upon Tyne, NE1 4LP, UK., Seddon JM; Department of Ophthalmology and Visual Sciences, University of Massachusetts Medical School, Worcester, MA 01655, USA., Kavanagh D; Complement Therapeutics Research Group, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK.; National Renal Complement Therapeutics Centre, Royal Victoria Infirmary, Newcastle upon Tyne, NE1 4LP, UK.
Jazyk:	angličtina
Zdroj:	Human molecular genetics [Hum Mol Genet] 2021 Jun 17; Vol. 30 (13), pp. 1188-1199.
DOI:	10.1093/hmg/ddab086
Abstrakt:	Age-related macular degeneration (AMD) is a complex neurodegenerative eye disease with behavioral and genetic etiology and is the leading cause of irreversible vision loss among elderly Caucasians. Functionally significant genetic variants in the alternative pathway of complement have been strongly linked to disease. More recently, a rare variant in the terminal pathway of complement has been associated with increased risk, Complement component 9 (C9) P167S. To assess the functional consequence of this variant, C9 levels were measured in two independent cohorts of AMD patients. In both cohorts, it was demonstrated that the P167S variant was associated with low C9 plasma levels. Further analysis showed that patients with advanced AMD had elevated sC5b-9 compared to those with non-advanced AMD, although this was not associated with the P167S polymorphism. Electron microscopy of membrane attack complexes (MACs) generated using recombinantly produced wild type or P167S C9 demonstrated identical MAC ring structures. In functional assays, the P167S variant displayed a higher propensity to polymerize and a small increase in its ability to induce hemolysis of sheep erythrocytes when added to C9-depleted serum. The demonstration that this C9 P167S AMD risk polymorphism displays increased polymerization and functional activity provides a rationale for the gene therapy trials of sCD59 to inhibit the terminal pathway of complement in AMD that are underway. (© The Author(s) 2021. Published by Oxford University Press.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu