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ORIGINAL RESEARCH article

Front. Immunol.
Sec. Molecular Innate Immunity
Volume 15 - 2024 | doi: 10.3389/fimmu.2024.1446081

Functional Evaluation of Rare Variants in Complement Factor I using a Minigene Assay

Provisionally accepted
Cobey J. Donelson Cobey J. Donelson Nicolo Ghiringhelli Borsa Nicolo Ghiringhelli Borsa Amanda O. Taylor Amanda O. Taylor Richard J. Smith Richard J. Smith *Yuzhou Zhang Yuzhou Zhang *
  • Molecular Otolaryngology and Renal Research Laboratories, The University of Iowa, Iowa City, Iowa, United States

The final, formatted version of the article will be published soon.

    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, 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 missense 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.

    Keywords: complement, alternative pathway, Complement Factor I, Complement-mediated diseases, Haploinsufficiency, RNA Splicing, Cis/trans-Acting Elements

    Received: 09 Jun 2024; Accepted: 30 Jul 2024.

    Copyright: © 2024 Donelson, Ghiringhelli Borsa, Taylor, Smith and Zhang. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence:
    Richard J. Smith, Molecular Otolaryngology and Renal Research Laboratories, The University of Iowa, Iowa City, IA 52242, Iowa, United States
    Yuzhou Zhang, Molecular Otolaryngology and Renal Research Laboratories, The University of Iowa, Iowa City, IA 52242, Iowa, United States

    Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.