Functional Characterization of Rare Genetic Variants in the N-Terminus of Complement Factor H in aHUS, C3G, and AMD

Membranoproliferative glomerulonephritis (MPGN), C3 glomerulopathy (C3G), atypical haemolytic uraemic syndrome (aHUS) and age-related macular degeneration (AMD) have all been strongly linked with dysfunction of the alternative pathway (AP) of complement. A significant proportion of individuals with...

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Veröffentlicht in:Frontiers in immunology Jg. 11; S. 602284
Hauptverfasser: Wong, Edwin K. S., Hallam, Thomas M., Brocklebank, Vicky, Walsh, Patrick R., Smith-Jackson, Kate, Shuttleworth, Victoria G., Cox, Thomas E., Anderson, Holly E., Barlow, Paul Nigel, Marchbank, Kevin James, Harris, Claire L., Kavanagh, David
Format: Journal Article
Sprache:Englisch
Veröffentlicht: Switzerland Frontiers Media S.A 14.01.2021
Schlagworte:
age-related macular degeneration
aHUS
Atypical Hemolytic Uremic Syndrome - genetics
C3G
complement factor H
Complement Factor H - chemistry
Complement Factor H - genetics
Genetic Variation
Glomerulonephritis, Membranoproliferative - genetics
Humans
Immunology
Macular Degeneration - genetics
MPGN
aHUS
age-related macular degeneration
C3G
MPGN
complement factor H
ISSN:1664-3224, 1664-3224
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Zusammenfassung:Membranoproliferative glomerulonephritis (MPGN), C3 glomerulopathy (C3G), atypical haemolytic uraemic syndrome (aHUS) and age-related macular degeneration (AMD) have all been strongly linked with dysfunction of the alternative pathway (AP) of complement. A significant proportion of individuals with MPGN, C3G, aHUS and AMD carry rare genetic variants in the CFH gene that cause functional or quantitative deficiencies in the factor H (FH) protein, an important regulator of the AP. In silico analysis of the deleteriousness of rare genetic variants in CFH is not reliable and careful biochemical assessment remains the gold standard. Six N-terminal variants of uncertain significance in CFH were identified in patients with these diseases of the AP and selected for analysis. The variants were produced in Pichia Pastoris in the setting of FH CCPs 1–4, purified by nickel affinity chromatography and size exclusion and characterized by surface plasmon resonance and haemolytic assays as well as by cofactor assays in the fluid phase. A single variant, Q81P demonstrated a profound loss of binding to C3b with consequent loss of cofactor and decay accelerating activity. A further 2 variants, G69E and D130N, demonstrated only subtle defects which could conceivably over time lead to disease progression of more chronic AP diseases such as C3G and AMD. In the variants S159N, A161S, and M162V any functional defect was below the capacity of the experimental assays to reliably detect. This study further underlines the importance of careful biochemical assessment when assigning functional consequences to rare genetic variants that may alter clinical decisions for patients.
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Edited by: Nicole Thielens, UMR5075 Institut de Biologie Structurale (IBS), France
These authors have contributed equally to this work
This article was submitted to Molecular Innate Immunity, a section of the journal Frontiers in Immunology
Reviewed by: Margarita López-Trascasa, Autonomous University of Madrid, Spain; Christine Skerka, Leibniz Institute for Natural Product Research and Infection Biology, Germany
ISSN:1664-3224
1664-3224
DOI:10.3389/fimmu.2020.602284