Imperial College London
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Dr. Doryen Bubeck

Faculty of Natural Sciences, Department of Life Sciences

Professor in Structural Immunology
 
 
 
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Contact

 

+44 (0)20 7594 2989d.bubeck Website

 
 
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Location

 

506Sir Ernst Chain BuildingSouth Kensington Campus

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Summary

 

Publications

Citation

BibTex format

@article{Mc:2021:hmg/ddab086,
author = {Mc, Mahon O and Hallam, TM and Patel, S and Harris, CL and Menny, A and Zelek, WM and Widjajahakim, R and Java, A and Cox, T and Tzoumas, N and Steel, DHW and Shuttleworth, VG and Smith-Jackson, K and Brocklebank, V and Griffiths, H and Cree, AJ and Atkinson, JP and Lotery, AJ and Bubeck, D and Morgan, BP and Marchbank, KJ and Seddon, JM and Kavanagh, D},
doi = {hmg/ddab086},
journal = {Human Molecular Genetics},
pages = {1188--1199},
title = {The rare C9 P167S risk variant for age-related macular degeneration increases polymerization of the terminal component of the complement cascade},
url = {http://dx.doi.org/10.1093/hmg/ddab086},
volume = {30},
year = {2021}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - 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.
AU  - Mc,Mahon O
AU  - Hallam,TM
AU  - Patel,S
AU  - Harris,CL
AU  - Menny,A
AU  - Zelek,WM
AU  - Widjajahakim,R
AU  - Java,A
AU  - Cox,T
AU  - Tzoumas,N
AU  - Steel,DHW
AU  - Shuttleworth,VG
AU  - Smith-Jackson,K
AU  - Brocklebank,V
AU  - Griffiths,H
AU  - Cree,AJ
AU  - Atkinson,JP
AU  - Lotery,AJ
AU  - Bubeck,D
AU  - Morgan,BP
AU  - Marchbank,KJ
AU  - Seddon,JM
AU  - Kavanagh,D
DO  - hmg/ddab086
EP  - 1199
PY  - 2021///
SN  - 0964-6906
SP  - 1188
TI  - The rare C9 P167S risk variant for age-related macular degeneration increases polymerization of the terminal component of the complement cascade
T2  - Human Molecular Genetics
UR  - http://dx.doi.org/10.1093/hmg/ddab086
UR  - https://academic.oup.com/hmg/article/30/13/1188/6203636
UR  - http://hdl.handle.net/10044/1/88896
VL  - 30
ER  -
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