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Lookup NU author(s): Anneliza Andreadi, Dr Vicky Brocklebank, Professor Kevin MarchbankORCiD, Professor Claire Harris, Professor David KavanaghORCiD
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© 2024 The AuthorsRare variants (RVs) in the gene encoding the regulatory enzyme complement factor I (CFI; FI) that reduce protein function or levels increase age-related macular degeneration risk. A total of 3357 subjects underwent screening in the SCOPE natural history study for geographic atrophy secondary to age-related macular degeneration, including CFI sequencing and serum FI measurement. Eleven CFI RV genotypes that were challenging to categorize as type I (low serum level) or type II (normal serum level, reduced enzymatic function) were characterized in the context of pure FI protein in C3b and C4b fluid phase cleavage assays and a novel bead-based functional assay (BBFA) of C3b cleavage. Four variants predicted or previously characterized as benign were analyzed by BBFA for comparison. In all, three variants (W51S, C67R, and I370T) resulted in low expression. Furthermore, four variants (P64L, R339Q, G527V, and P528T) were identified as being highly deleterious with IC50s for C3b breakdown >1 log increased versus the WT protein, while two variants (K476E and R474Q) were ∼1 log reduced in function. Meanwhile, six variants (P50A, T203I, K441R, E548Q, P553S, and S570T) had IC50s similar to WT. Odds ratios and BBFA IC50s were positively correlated (r = 0.76, p < 0.01), while odds ratios versus combined annotation dependent depletion (CADD) scores were not (r = 0.43, p = 0.16). Overall, 15 CFI RVs were functionally characterized which may aid future patient stratification for complement-targeted therapies. Pure protein in vitro analysis remains the gold standard for determining the functional consequence of CFI RVs.
Author(s): Hallam TM, Andreadi A, Sharp SJ, Brocklebank V, Gardenal E, Dreismann A, Arora R, Dennis M, Flaxel C, Hall E, Hoyng C, Charbel Issa P, Leveziel N, Molnar F, Navarro R, Schneiderman T, Steel D, Tadayoni R, Tezel T, Weber M, Lotery AJ, Marchbank KJ, Harris CL, Jones AV, Kavanagh D
Publication type: Article
Publication status: Published
Journal: Journal of Biological Chemistry
Year: 2024
Volume: 300
Issue: 7
Online publication date: 07/06/2024
Acceptance date: 02/04/2018
Date deposited: 17/07/2024
ISSN (print): 0021-9258
ISSN (electronic): 1083-351X
Publisher: American Society for Biochemistry and Molecular Biology Inc.
URL: https://doi.org/10.1016/j.jbc.2024.107452
DOI: 10.1016/j.jbc.2024.107452
PubMed id: 38852887
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