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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.

Lookup NU author(s): Tom Hallam, Professor Claire Harris, Nik Tzoumas, David Steel, Victoria Shuttleworth, Dr Kate Smith-Jackson, Dr Vicky Brocklebank, Professor Kevin Marchbank, Professor David Kavanagh

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


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.


Publication metadata

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

Pages: ePub ahead of print

Online publication date: 30/03/2021

Acceptance date: 02/04/2018

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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