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Effect of rare coding variants in the CFI gene on Factor I expression levels
Sarah de Jong1, Elena B Volokhina2,3,4, Anita de Breuk1
1Department of Ophthalmology, Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands.
Human Molecular Genetics
|June 9, 2020
Summary
Rare variants in the complement factor I (CFI) gene significantly reduce Factor I (FI) expression. Over half of tested CFI variants impair complement regulation, aiding clinical interpretation for conditions like AMD.
Area of Science:
- Immunology
- Genetics
Background:
- Complement factor I (FI) is a key regulator of complement activity.
- Rare coding variants in the complement factor I (CFI) gene are linked to various diseases, including age-related macular degeneration, atypical hemolytic uremic syndrome, and C3 glomerulopathy.
- The clinical significance of many CFI variants remains unknown.
Purpose of the Study:
- To investigate the impact of rare coding variants in the CFI gene on FI expression levels.
- To correlate in vitro expression data with in vivo plasma levels in variant carriers.
Main Methods:
- Measured FI levels in plasma samples from 155 individuals carrying 24 different rare CFI variants.
- Assessed recombinant FI expression in epithelial cells for 126 rare coding variants.
- Correlated recombinant protein expression with plasma FI levels.
Main Results:
- Significantly reduced FI plasma levels were observed in carriers of specific variants (p.Gly119Arg, p.Leu131Arg, p.Gly188Ala, c.772G>A).
- 54% (68 out of 126) of tested rare CFI variants resulted in significantly reduced recombinant FI expression.
- Recombinant protein expression levels strongly correlated with FI levels in plasma.
Conclusions:
- More than half of rare coding CFI variants lead to reduced FI expression, potentially impairing complement regulation.
- This comprehensive analysis aids in interpreting the clinical significance of rare CFI variants.
- Findings are crucial for patient stratification in clinical trials for CFI gene therapy, particularly for age-related macular degeneration.
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