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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

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 (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.
0964-6906
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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Widjajahakim, R.
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Java, A.
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Cox, T.
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Tzoumas, N.
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Smith-Jackson, K.
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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.
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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), 1188-1199. (doi:10.1093/hmg/ddab086).

Record type: Article

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.

Text
ddab086 - Accepted Manuscript
Available under License Creative Commons Attribution.
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e-pub ahead of print date: 30 March 2021

Identifiers

Local EPrints ID: 448738
URI: http://eprints.soton.ac.uk/id/eprint/448738
ISSN: 0964-6906
PURE UUID: a62311d4-22ec-496a-8ff9-69cd451b12c5
ORCID for Andrew Lotery: ORCID iD orcid.org/0000-0001-5541-4305

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Date deposited: 04 May 2021 16:38
Last modified: 26 Nov 2021 02:47

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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: Andrew Lotery ORCID iD
Author: D. Bubeck
Author: B.P. Morgan
Author: K.J. Marchbank
Author: J.M. Seddon
Author: D. Kavanagh

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