June 2021
Volume 62, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2021
Comprehensive Analysis of Genetic Variants of Uncertain Significance in Complement Factor I (CFI) in Advanced Age Related Macular Degeneration (AAMD)
Author Affiliations & Notes
  • Anuja Java
    Department of Medicine, Washington University in St Louis, St Louis, Missouri, United States
    Department of Medicine, VA St Louis Medical Center John Cochran Division, Saint Louis, Missouri, United States
  • Rafael Widjajahakim
    Department of Ophthalmology and Visual Sciences, University of Massachusetts Medical School, Worcester, Massachusetts, United States
  • John Atkinson
    Department of Medicine, Washington University in St Louis, St Louis, Missouri, United States
  • Johanna M Seddon
    Department of Ophthalmology and Visual Sciences, University of Massachusetts Medical School, Worcester, Massachusetts, United States
  • Footnotes
    Commercial Relationships   Anuja Java, Alexion Pharmaceuticals (C), Gemini Therapeutics (C), Novartis Pharmaceuticals (C); Rafael Widjajahakim, None; John Atkinson, Achillion Pharmaceuticals (C), Annexon Biosciences (C), BioMarin Pharmaceutical (C), Celldex Therapeutics (C), Clinical Pharmacy Services (C), Compliment Corporation (I), Gemini Therapeutics (I), Kypha (I), Kypha (C), Q32BIO Inc (I), Q32BIO Inc (C); Johanna Seddon, Gemini Therapeutics (I), THEA (C)
  • Footnotes
    Support  Supported by NIH R01-EY011309, NIH R01- EY028602, American Macular Degeneration Foundation, Northampton, MA; The Macular Degeneration Center of Excellence, University of Massachusetts Medical School, Department of Ophthalmology and Visual Sciences, Worcester, MA (JS); NIH R01-EY028602 (JA & AJ), NIH 2R01 GM099111; NIH GM136352 (JA); Barnes Jewish Hospital Foundation Fund, Division of Nephrology, Washington University School of Medicine in St. Louis (AJ).
Investigative Ophthalmology & Visual Science June 2021, Vol.62, 257. doi:
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    • Get Citation

      Anuja Java, Rafael Widjajahakim, John Atkinson, Johanna M Seddon; Comprehensive Analysis of Genetic Variants of Uncertain Significance in Complement Factor I (CFI) in Advanced Age Related Macular Degeneration (AAMD). Invest. Ophthalmol. Vis. Sci. 2021;62(8):257.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : Factor I (FI) is a serine protease inhibitor of the alternative pathway of the complement system. This regulation of the complement system is achieved by cleavage of C3b (known as cofactor activity). Heterozygous rare genetic variants in CFI are associated with AAMD. The clinical impact of these variants is unknown since a majority have not been functionally characterized and are classified based on predictive models as ‘variants of uncertain significance’ (VUS). This study assessed the functional significance of VUS in CFI.

Methods :
Our previous cross-sectional study demonstrated that heterozygous CFI variants in AAMD can be categorized into three major types [Java et al. Trans Vis Sci Tech 2020; 9(9):37]. Type 1 variants caused a quantitative deficiency of FI (decreased FI level with a proportional decrease in function). Type 2 variants demonstrated a qualitative deficiency (normal FI level but decreased function). However, Type 3 variants consisted of VUS that were less dysfunctional than Types 1 and 2 but were not as biologically active as wild-type. In this study we present an in-depth functional assessment of the Type 3 variants. We utilized serum FI antigenic levels, site-directed mutagenesis followed by expression of the recombinant variant and a comprehensive set of functional assays to characterize nine Type 3 variants identified in 34 individuals (R202I, Q217H, S221Y, G263V, G362A, K441R, Q462H, I492L and N536K).

Results : Our study established that the expression of the recombinant protein compared to wild-type by 293T cells was reduced for Q217H, S221Y and G263V. Further, R202I and G362A had significantly reduced cofactor activity. These results led to recategorization of Q217H, S221Y and G263V as Type 1 variants and to reclassification of R202I and G362A as Type 2. The remaining Type 3 variants (K441R, Q462H, I492L and N536K) are best classified as being benign at this time. This study highlights the utility of an in-depth functional analysis in defining the pathologic and clinical implications of complement variants in AAMD and provides further insights relative to the pathogenic mechanisms underlying AMD.

Conclusions : This approach will be a useful model system for guiding more appropriate therapeutic decisions relative to an individualized treatment plan for patients and thereby pave the way for precision medicine in AMD.

This is a 2021 ARVO Annual Meeting abstract.

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