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Gain-of-Function Mutations R249C and S250C in Complement C2 Protein Increase C3 Deposition in the Presence of C-Reactive Protein

The impairment of the alternative complement pathway contributes to rare kidney diseases such as atypical hemolytic uremic syndrome (aHUS) and C3 glomerulopathy (C3G). We recently described an aHUS patient carrying an exceptional gain-of-function (GoF) mutation (S250C) in the classical complement pa...

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Autores principales: Urban, Aleksandra, Kowalska, Daria, Stasiłojć, Grzegorz, Kuźniewska, Alicja, Skrobińska, Anna, Arjona, Emilia, Alonso, Eugenia Castellote, Fenollosa Segarra, María Ángeles, Jongerius, Ilse, Spaapen, Robbert, Satchell, Simon, Thiel, Marcel, Ołdziej, Stanisław, Rodriguez de Córdoba, Santiago, Okrój, Marcin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8654806/
https://www.ncbi.nlm.nih.gov/pubmed/34899688
http://dx.doi.org/10.3389/fimmu.2021.724361
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author Urban, Aleksandra
Kowalska, Daria
Stasiłojć, Grzegorz
Kuźniewska, Alicja
Skrobińska, Anna
Arjona, Emilia
Alonso, Eugenia Castellote
Fenollosa Segarra, María Ángeles
Jongerius, Ilse
Spaapen, Robbert
Satchell, Simon
Thiel, Marcel
Ołdziej, Stanisław
Rodriguez de Córdoba, Santiago
Okrój, Marcin
author_facet Urban, Aleksandra
Kowalska, Daria
Stasiłojć, Grzegorz
Kuźniewska, Alicja
Skrobińska, Anna
Arjona, Emilia
Alonso, Eugenia Castellote
Fenollosa Segarra, María Ángeles
Jongerius, Ilse
Spaapen, Robbert
Satchell, Simon
Thiel, Marcel
Ołdziej, Stanisław
Rodriguez de Córdoba, Santiago
Okrój, Marcin
author_sort Urban, Aleksandra
collection PubMed
description The impairment of the alternative complement pathway contributes to rare kidney diseases such as atypical hemolytic uremic syndrome (aHUS) and C3 glomerulopathy (C3G). We recently described an aHUS patient carrying an exceptional gain-of-function (GoF) mutation (S250C) in the classical complement pathway component C2 leading to the formation of hyperactive classical convertases. We now report the identification of the same mutation and another C2 GoF mutation R249C in two other patients with a glomerulopathy of uncertain etiology. Both mutations stabilize the classical C3 convertases by a similar mechanism. The presence of R249C and S250C variants in serum increases complement-dependent cytotoxicity (CDC) in antibody-sensitized human cells and elevates deposition of C3 on ELISA plates coated with C-reactive protein (CRP), as well as on the surface of glomerular endothelial cells. Our data justify the inclusion of classical pathway genes in the genetic analysis of patients suspected of complement-driven renal disorders. Also, we point out CRP as a potential antibody-independent trigger capable of driving excessive complement activation in carriers of the GoF mutations in complement C2.
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spelling pubmed-86548062021-12-10 Gain-of-Function Mutations R249C and S250C in Complement C2 Protein Increase C3 Deposition in the Presence of C-Reactive Protein Urban, Aleksandra Kowalska, Daria Stasiłojć, Grzegorz Kuźniewska, Alicja Skrobińska, Anna Arjona, Emilia Alonso, Eugenia Castellote Fenollosa Segarra, María Ángeles Jongerius, Ilse Spaapen, Robbert Satchell, Simon Thiel, Marcel Ołdziej, Stanisław Rodriguez de Córdoba, Santiago Okrój, Marcin Front Immunol Immunology The impairment of the alternative complement pathway contributes to rare kidney diseases such as atypical hemolytic uremic syndrome (aHUS) and C3 glomerulopathy (C3G). We recently described an aHUS patient carrying an exceptional gain-of-function (GoF) mutation (S250C) in the classical complement pathway component C2 leading to the formation of hyperactive classical convertases. We now report the identification of the same mutation and another C2 GoF mutation R249C in two other patients with a glomerulopathy of uncertain etiology. Both mutations stabilize the classical C3 convertases by a similar mechanism. The presence of R249C and S250C variants in serum increases complement-dependent cytotoxicity (CDC) in antibody-sensitized human cells and elevates deposition of C3 on ELISA plates coated with C-reactive protein (CRP), as well as on the surface of glomerular endothelial cells. Our data justify the inclusion of classical pathway genes in the genetic analysis of patients suspected of complement-driven renal disorders. Also, we point out CRP as a potential antibody-independent trigger capable of driving excessive complement activation in carriers of the GoF mutations in complement C2. Frontiers Media S.A. 2021-11-25 /pmc/articles/PMC8654806/ /pubmed/34899688 http://dx.doi.org/10.3389/fimmu.2021.724361 Text en Copyright © 2021 Urban, Kowalska, Stasiłojć, Kuźniewska, Skrobińska, Arjona, Alonso, Fenollosa Segarra, Jongerius, Spaapen, Satchell, Thiel, Ołdziej, Rodriguez de Córdoba and Okrój https://creativecommons.org/licenses/by/4.0/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) and the copyright owner(s) 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.
spellingShingle Immunology
Urban, Aleksandra
Kowalska, Daria
Stasiłojć, Grzegorz
Kuźniewska, Alicja
Skrobińska, Anna
Arjona, Emilia
Alonso, Eugenia Castellote
Fenollosa Segarra, María Ángeles
Jongerius, Ilse
Spaapen, Robbert
Satchell, Simon
Thiel, Marcel
Ołdziej, Stanisław
Rodriguez de Córdoba, Santiago
Okrój, Marcin
Gain-of-Function Mutations R249C and S250C in Complement C2 Protein Increase C3 Deposition in the Presence of C-Reactive Protein
title Gain-of-Function Mutations R249C and S250C in Complement C2 Protein Increase C3 Deposition in the Presence of C-Reactive Protein
title_full Gain-of-Function Mutations R249C and S250C in Complement C2 Protein Increase C3 Deposition in the Presence of C-Reactive Protein
title_fullStr Gain-of-Function Mutations R249C and S250C in Complement C2 Protein Increase C3 Deposition in the Presence of C-Reactive Protein
title_full_unstemmed Gain-of-Function Mutations R249C and S250C in Complement C2 Protein Increase C3 Deposition in the Presence of C-Reactive Protein
title_short Gain-of-Function Mutations R249C and S250C in Complement C2 Protein Increase C3 Deposition in the Presence of C-Reactive Protein
title_sort gain-of-function mutations r249c and s250c in complement c2 protein increase c3 deposition in the presence of c-reactive protein
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8654806/
https://www.ncbi.nlm.nih.gov/pubmed/34899688
http://dx.doi.org/10.3389/fimmu.2021.724361
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