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

Mc Mahon, O., Hallam, T. M., Patel, S., Harris, C. L., Menny, A., Zelek, W. M., Widjajahakim, R., Java, A., Cox, T., Tzoumas, N., Steel, D. H. W., Shuttleworth, V. G., Smith-Jackson, K., Brocklebank, V., Griffiths, H., Cree, A. J., Atkinson, J. P., Lotery, A. J., Bubeck, D., Morgan, B. P., Marchbank, K. J., Seddon, J. M. and Kavanagh, D. 2021. The rare C9 P167S risk variant for age-related macular degeneration increases polymerization of the terminal component of the complement cascade. Human Molecular Genetics 30 (13) , pp. 1188-1199. 10.1093/hmg/ddab086

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Abstract

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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Additional Information: This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/)
Publisher: Oxford University Press
ISSN: 0964-6906
Date of First Compliant Deposit: 4 May 2021
Date of Acceptance: 30 March 2021
Last Modified: 21 Jul 2021 11:03
URI: http://orca.cardiff.ac.uk/id/eprint/140885

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