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Lookup NU author(s): Tom Hallam, Gladys -, Nik Tzoumas, David Steel, Victoria Shuttleworth, Dr Kate Smith-Jackson, Dr Vicky Brocklebank, Professor Kevin MarchbankORCiD, Professor David KavanaghORCiD
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
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 (MAC) 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 polymerise and a small increase in its ability to induce haemolysis of sheep erythrocytes when added to C9-depleted serum. The demonstration that this C9 P167S AMD risk polymorphism displays increased polymerisation 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.
Author(s): McMahon O, Hallam TM, Patel S, Harris CL, Menny A, Zelek WM, Widjajahakim R, Java A, Tzoumas N, Steel DHW, Shuttleworth VG, Smith-Jackson K, Brocklebank V, Griffiths H, Cree AJ, Atkinson JP, Lotery AJ, Bubeck D, Morgan BP, Marchbank KJ, Seddon JM, Kavanagh D
Publication type: Article
Publication status: Published
Journal: Human Molecular Genetics
Year: 2021
Volume: 30
Issue: 13
Pages: 1188-1199
Print publication date: 01/07/2021
Online publication date: 30/03/2021
Acceptance date: 22/03/2021
Date deposited: 23/04/2021
ISSN (print): 0964-6906
ISSN (electronic): 1460-2083
Publisher: Oxford University Press
URL: https://doi.org/10.1093/hmg/ddab086
DOI: 10.1093/hmg/ddab086
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