Department of Ophthalmology and Visual Sciences
Eye Diseases | Medical Genetics | Molecular Genetics | Ophthalmology
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.
hemolysis, polymorphism, erythrocytes, complement system proteins, tissue membrane, plasma, sheep, genetics, age-related macular degeneration, older adult, polymerization, complex
Rights and Permissions
Copyright © The Author(s) 2021. Published by Oxford University Press. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
DOI of Published Version
McMahon O, Hallam TM, Patel S, Harris CL, Menny A, Zelek WM, Widjajahakim R, Java A, Cox TE, 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. The rare C9 P167S risk variant for age-related macular degeneration increases polymerization of the terminal component of the complement cascade. Hum Mol Genet. 2021 Jun 17;30(13):1188-1199. doi: 10.1093/hmg/ddab086. PMID: 33783477; PMCID: PMC8212764. Link to article on publisher's site
Human molecular genetics
McMahon O, Patel S, Widjajahakim R, Seddon JM, Kavanagh D. (2021). The rare C9 P167S risk variant for age-related macular degeneration increases polymerization of the terminal component of the complement cascade. Open Access Publications by UMass Chan Authors. https://doi.org/10.1093/hmg/ddab086. Retrieved from https://escholarship.umassmed.edu/oapubs/4788
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.