Journal article
Functional evaluation of rare variants in complement factor I using a minigene assay
Frontiers in immunology, Vol.15, 1446081
08/01/2024
DOI: 10.3389/fimmu.2024.1446081
PMCID: PMC11374653
PMID: 39238643
Abstract
The regulatory serine protease, complement factor I (FI), in conjunction with one of its cofactors (FH, C4BP, MCP, or CR1), plays an essential role in controlling complement activity through inactivation of C3b and C4b. The functional impact by missense variants in the CFI gene, particularly those with minor allele frequencies of 0.01% to 0.1%, is infrequently studied. As such, these variants are typically classified as variants of uncertain significance (VUS) when they are identified by clinical testing. Herein, we utilized a minigene splicing assay to assess the functional impact of 36 ultra-rare variants of CFI. These variants were selected based on their minor allele frequencies (MAF) and their association with low-normal FI levels. Four variants lead to aberrant splicing–one 5’ consensus splice site (NM_000204.5: c.1429G>C, p.Asp477His) and three exonic changes (c.355G>A, p.Gly119Arg; c.472G>A, p.Gly158Arg; and c.950G>A, p.Arg317Gln)–enabling their reclassification to likely pathogenic (LP) or pathogenic (P) based on ACMG guidelines. These findings underscore the value of functional assays, such as the minigene assay, in assessing the clinical relevance of rare variants in CFI.
Details
- Title: Subtitle
- Functional evaluation of rare variants in complement factor I using a minigene assay
- Creators
- Cobey J. H. DonelsonNicolo Ghiringhelli BorsaAmanda O. TaylorRichard J. H. SmithYuzhou Zhang
- Resource Type
- Journal article
- Publication Details
- Frontiers in immunology, Vol.15, 1446081
- DOI
- 10.3389/fimmu.2024.1446081
- PMID
- 39238643
- PMCID
- PMC11374653
- NLM abbreviation
- Front Immunol
- ISSN
- 1664-3224
- eISSN
- 1664-3224
- Publisher
- Frontiers Media S.A
- Grant note
This project could not have been accomplished without the support from the research assistants and staff of the University of Iowa Molecular Otolaryngology and Renal Research Laboratories. Special acknowledgment goes to Amanda Odell and Dr. Adela M. Mansilla, whose expertise was crucial in variant classification following ACMG guidelines, and to Stephen Presti for his work in determining the effects of the common SNP in CFI. An additional acknowledgment is extended to Drs. Hela Azaiez and Kevin Booth for providing a prototypical minigene protocol at the start of this project.
- Language
- English
- Date published
- 08/01/2024
- Academic Unit
- Roy J. Carver Department of Biomedical Engineering; Molecular Physiology and Biophysics; Anatomy and Cell Biology; Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Otolaryngology; Internal Medicine
- Record Identifier
- 9984699050702771
Metrics
10 Record Views