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Effect of rare coding variants in the CFI gene on Factor I expression levels

de Jong, Sarah LU ; Volokhina, Elena B. LU ; de Breuk, Anita ; Nilsson, Sara C. LU ; de Jong, Eiko K. ; van der Kar, Nicole C.A.J. ; Bakker, Bjorn ; Hoyng, Carel B. ; van den Heuvel, Lambert P. and Blom, Anna M. LU orcid , et al. (2020) In Human Molecular Genetics 29(14). p.2313-2324
Abstract

Factor I (FI) is one of the main inhibitors of complement activity, and numerous rare coding variants have been reported in patients with age-related macular degeneration, atypical hemolytic uremic syndrome and C3 glomerulopathy. Since many of these variants are of unknown clinical significance, this study aimed to determine the effect of rare coding variants in the complement factor I (CFI) gene on FI expression. We measured FI levels in plasma samples of carriers of rare coding variants and in vitro in the supernatants of epithelial cells expressing recombinant FI. FI levels were measured in 177 plasma samples of 155 individuals, carrying 24 different rare coding variants in CFI. In carriers of the variants p.Gly119Arg, p.Leu131Arg,... (More)

Factor I (FI) is one of the main inhibitors of complement activity, and numerous rare coding variants have been reported in patients with age-related macular degeneration, atypical hemolytic uremic syndrome and C3 glomerulopathy. Since many of these variants are of unknown clinical significance, this study aimed to determine the effect of rare coding variants in the complement factor I (CFI) gene on FI expression. We measured FI levels in plasma samples of carriers of rare coding variants and in vitro in the supernatants of epithelial cells expressing recombinant FI. FI levels were measured in 177 plasma samples of 155 individuals, carrying 24 different rare coding variants in CFI. In carriers of the variants p.Gly119Arg, p.Leu131Arg, p.Gly188Ala and c.772G>A (r.685_773del), significantly reduced FI plasma levels were detected. Furthermore, recombinant FI expression levels were determined for 126 rare coding variants. Of these variants 68 (54%) resulted in significantly reduced FI expression in supernatant compared to wildtype (WT). The recombinant protein expression levels correlated significantly with the FI level in plasma of carriers of CFI variants. In this study, we performed the most comprehensive FI expression level analysis of rare coding variants in CFI to date. More than half of CFI variants lead to reduced FI expression, which might impair complement regulation in vivo. Our study will aid the interpretation of rare coding CFI variants identified in clinical practice, which is in particular important in light of patient inclusion in ongoing clinical trials for CFI gene supplementation in AMD.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Human Molecular Genetics
volume
29
issue
14
pages
12 pages
publisher
Oxford University Press
external identifiers
  • scopus:85089615567
  • pmid:32510551
ISSN
0964-6906
DOI
10.1093/hmg/ddaa114
language
English
LU publication?
yes
id
d4fcefec-916e-4b43-ad90-8627e9cd3990
date added to LUP
2020-08-27 12:56:34
date last changed
2024-06-26 21:10:36
@article{d4fcefec-916e-4b43-ad90-8627e9cd3990,
  abstract     = {{<p>Factor I (FI) is one of the main inhibitors of complement activity, and numerous rare coding variants have been reported in patients with age-related macular degeneration, atypical hemolytic uremic syndrome and C3 glomerulopathy. Since many of these variants are of unknown clinical significance, this study aimed to determine the effect of rare coding variants in the complement factor I (CFI) gene on FI expression. We measured FI levels in plasma samples of carriers of rare coding variants and in vitro in the supernatants of epithelial cells expressing recombinant FI. FI levels were measured in 177 plasma samples of 155 individuals, carrying 24 different rare coding variants in CFI. In carriers of the variants p.Gly119Arg, p.Leu131Arg, p.Gly188Ala and c.772G&gt;A (r.685_773del), significantly reduced FI plasma levels were detected. Furthermore, recombinant FI expression levels were determined for 126 rare coding variants. Of these variants 68 (54%) resulted in significantly reduced FI expression in supernatant compared to wildtype (WT). The recombinant protein expression levels correlated significantly with the FI level in plasma of carriers of CFI variants. In this study, we performed the most comprehensive FI expression level analysis of rare coding variants in CFI to date. More than half of CFI variants lead to reduced FI expression, which might impair complement regulation in vivo. Our study will aid the interpretation of rare coding CFI variants identified in clinical practice, which is in particular important in light of patient inclusion in ongoing clinical trials for CFI gene supplementation in AMD.</p>}},
  author       = {{de Jong, Sarah and Volokhina, Elena B. and de Breuk, Anita and Nilsson, Sara C. and de Jong, Eiko K. and van der Kar, Nicole C.A.J. and Bakker, Bjorn and Hoyng, Carel B. and van den Heuvel, Lambert P. and Blom, Anna M. and den Hollander, Anneke I.}},
  issn         = {{0964-6906}},
  language     = {{eng}},
  number       = {{14}},
  pages        = {{2313--2324}},
  publisher    = {{Oxford University Press}},
  series       = {{Human Molecular Genetics}},
  title        = {{Effect of rare coding variants in the CFI gene on Factor I expression levels}},
  url          = {{http://dx.doi.org/10.1093/hmg/ddaa114}},
  doi          = {{10.1093/hmg/ddaa114}},
  volume       = {{29}},
  year         = {{2020}},
}