
PMID- 32510551
OWN - NLM
STAT- MEDLINE
DCOM- 20210818
LR  - 20210818
IS  - 1460-2083 (Electronic)
IS  - 0964-6906 (Print)
IS  - 0964-6906 (Linking)
VI  - 29
IP  - 14
DP  - 2020 Aug 11
TI  - Effect of rare coding variants in the CFI gene on Factor I expression levels.
PG  - 2313-2324
LID - 10.1093/hmg/ddaa114 [doi]
AB  - 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.
CI  - (c) The Author(s) 2020. Published by Oxford University Press. All rights reserved. 
      For Permissions, please email: journals.permissions@oup.com.
FAU - de Jong, Sarah
AU  - de Jong S
AD  - Department of Ophthalmology, Donders Institute for Brain, Cognition and Behavior, 
      Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands.
FAU - Volokhina, Elena B
AU  - Volokhina EB
AD  - Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 
      6525 GA Nijmegen, The Netherlands.
AD  - Amalia Children's Hospital, Radboud University Medical Center, 6525 GA Nijmegen, 
      The Netherlands.
AD  - Department of Laboratory Medicine, Radboud University Medical Center, 6525 GA 
      Nijmegen, The Netherlands.
FAU - de Breuk, Anita
AU  - de Breuk A
AD  - Department of Ophthalmology, Donders Institute for Brain, Cognition and Behavior, 
      Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands.
FAU - Nilsson, Sara C
AU  - Nilsson SC
AD  - Department of Translational Medicine, Lund University, 21428 Malmo, Sweden.
FAU - de Jong, Eiko K
AU  - de Jong EK
AD  - Department of Ophthalmology, Donders Institute for Brain, Cognition and Behavior, 
      Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands.
FAU - van der Kar, Nicole C A J
AU  - van der Kar NCAJ
AD  - Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 
      6525 GA Nijmegen, The Netherlands.
AD  - Amalia Children's Hospital, Radboud University Medical Center, 6525 GA Nijmegen, 
      The Netherlands.
FAU - Bakker, Bjorn
AU  - Bakker B
AD  - Department of Ophthalmology, Donders Institute for Brain, Cognition and Behavior, 
      Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands.
FAU - Hoyng, Carel B
AU  - Hoyng CB
AD  - Department of Ophthalmology, Donders Institute for Brain, Cognition and Behavior, 
      Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands.
FAU - van den Heuvel, Lambert P
AU  - van den Heuvel LP
AD  - Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 
      6525 GA Nijmegen, The Netherlands.
AD  - Department of Laboratory Medicine, Radboud University Medical Center, 6525 GA 
      Nijmegen, The Netherlands.
FAU - Blom, Anna M
AU  - Blom AM
AD  - Department of Translational Medicine, Lund University, 21428 Malmo, Sweden.
FAU - den Hollander, Anneke I
AU  - den Hollander AI
AD  - Department of Ophthalmology, Donders Institute for Brain, Cognition and Behavior, 
      Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - Hum Mol Genet
JT  - Human molecular genetics
JID - 9208958
RN  - 9001-32-5 (Fibrinogen)
RN  - EC 3.4.21.45 (Complement Factor I)
SB  - IM
MH  - Aged
MH  - Aged, 80 and over
MH  - Alleles
MH  - Atypical Hemolytic Uremic Syndrome/blood/*genetics/pathology
MH  - Complement Factor I/*genetics
MH  - Female
MH  - Fibrinogen/*genetics
MH  - Gene Expression Regulation/genetics
MH  - Genetic Predisposition to Disease
MH  - Genotype
MH  - Heterozygote
MH  - Humans
MH  - Macular Degeneration/blood/*genetics/pathology
MH  - Male
MH  - Middle Aged
MH  - Polymorphism, Single Nucleotide/genetics
PMC - PMC7424754
EDAT- 2020/06/09 06:00
MHDA- 2021/08/19 06:00
PMCR- 2020/06/08
CRDT- 2020/06/09 06:00
PHST- 2020/03/18 00:00 [received]
PHST- 2020/05/29 00:00 [revised]
PHST- 2020/06/03 00:00 [accepted]
PHST- 2020/06/09 06:00 [pubmed]
PHST- 2021/08/19 06:00 [medline]
PHST- 2020/06/09 06:00 [entrez]
PHST- 2020/06/08 00:00 [pmc-release]
AID - 5854562 [pii]
AID - ddaa114 [pii]
AID - 10.1093/hmg/ddaa114 [doi]
PST - ppublish
SO  - Hum Mol Genet. 2020 Aug 11;29(14):2313-2324. doi: 10.1093/hmg/ddaa114.
