The rare C9 P167S risk variant for age-related macular degeneration increases polymerization of the terminal component of the complement cascade
The rare C9 P167S risk variant for age-related macular degeneration increases polymerization of the terminal component of the complement cascade
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.
1188-1199
McMahon, O.
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Hallam, T.M.
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Patel, S.
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Harris, C.L.
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Menny, A.
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Zelek, W.M.
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Widjajahakim, R.
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Java, A.
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Cox, T.
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Tzoumas, N.
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Steel, D.H.W.
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Shuttleworth, V.G.
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Smith-Jackson, K.
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V., Brocklebank
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Griffiths, H.
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Cree, A.J.
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Atkinson, J.P.
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Lotery, Andrew
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Bubeck, D.
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Morgan, B.P.
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Marchbank, K.J.
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Seddon, J.M.
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Kavanagh, D.
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1 July 2021
McMahon, O.
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Hallam, T.M.
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Patel, S.
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Harris, C.L.
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Menny, A.
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Zelek, W.M.
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Widjajahakim, R.
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Java, A.
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Cox, T.
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Tzoumas, N.
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Steel, D.H.W.
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Shuttleworth, V.G.
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Smith-Jackson, K.
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V., Brocklebank
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Griffiths, H.
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Cree, A.J.
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Atkinson, J.P.
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Lotery, Andrew
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Bubeck, D.
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Morgan, B.P.
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Marchbank, K.J.
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Seddon, J.M.
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Kavanagh, D.
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McMahon, 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., V., Brocklebank, Griffiths, H., Cree, A.J., Atkinson, J.P., Lotery, Andrew, 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), .
(doi:10.1093/hmg/ddab086).
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 (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.
Text
ddab086
- Accepted Manuscript
More information
e-pub ahead of print date: 30 March 2021
Published date: 1 July 2021
Additional Information:
Funding Information:
NIHR Newcastle Biomedical Research Centre at Newcastle upon Tyne Hospitals NHS Foundation Trust; J.M.S was funded by US National Institutes of Health (grants R01-EY011309 and R01-EY028602), American Macular Degeneration Foundation, and Macular Degeneration Research Fund, University of Massachusetts Medical School, Worcester, MA, USA (J.M.S.); K.J.M. was funded by the Northern Counties Kidney Research Fund, the Newcastle Healthcare Charites and a Kidney Research UK project grant (RP7/2015). D.K. was funded by Fight for Sight (1564/1565), the Wellcome Trust, the Medical Research Council and Kidney Research UK. T.M.H. was funded by Complement UK; T.E.C. is funded by MRC Discovery Medicine North; A.J.L. is an NIHR Senior Investigator. C.L.H. was funded by Newcastle University. D.B. and A.M. was supported by a CRUK Career Establishment Award (C26409/A16099) to D.B.
Publisher Copyright:
© 2021 The Author(s). Published by Oxford University Press.
Identifiers
Local EPrints ID: 448738
URI: http://eprints.soton.ac.uk/id/eprint/448738
ISSN: 0964-6906
PURE UUID: a62311d4-22ec-496a-8ff9-69cd451b12c5
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Date deposited: 04 May 2021 16:38
Last modified: 17 Mar 2024 02:57
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Contributors
Author:
O. McMahon
Author:
T.M. Hallam
Author:
S. Patel
Author:
C.L. Harris
Author:
A. Menny
Author:
W.M. Zelek
Author:
R. Widjajahakim
Author:
A. Java
Author:
T. Cox
Author:
N. Tzoumas
Author:
D.H.W. Steel
Author:
V.G. Shuttleworth
Author:
K. Smith-Jackson
Author:
Brocklebank V.
Author:
H. Griffiths
Author:
A.J. Cree
Author:
J.P. Atkinson
Author:
D. Bubeck
Author:
B.P. Morgan
Author:
K.J. Marchbank
Author:
J.M. Seddon
Author:
D. Kavanagh
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