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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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2021-11-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2021.724361/full |
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| author | Aleksandra Urban Daria Kowalska Grzegorz Stasiłojć Alicja Kuźniewska Anna Skrobińska Emilia Arjona Eugenia Castellote Alonso María Ángeles Fenollosa Segarra Ilse Jongerius Ilse Jongerius Robbert Spaapen Simon Satchell Marcel Thiel Stanisław Ołdziej Santiago Rodriguez de Córdoba Marcin Okrój |
| author_facet | Aleksandra Urban Daria Kowalska Grzegorz Stasiłojć Alicja Kuźniewska Anna Skrobińska Emilia Arjona Eugenia Castellote Alonso María Ángeles Fenollosa Segarra Ilse Jongerius Ilse Jongerius Robbert Spaapen Simon Satchell Marcel Thiel Stanisław Ołdziej Santiago Rodriguez de Córdoba Marcin Okrój |
| author_sort | Aleksandra Urban |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-12-14T12:55:08Z |
| format | Article |
| id | doaj.art-717a2faa64dc496784006a113f6cb136 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-12-14T12:55:08Z |
| publishDate | 2021-11-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-717a2faa64dc496784006a113f6cb1362022-12-21T23:00:35ZengFrontiers Media S.A.Frontiers in Immunology1664-32242021-11-011210.3389/fimmu.2021.724361724361Gain-of-Function Mutations R249C and S250C in Complement C2 Protein Increase C3 Deposition in the Presence of C-Reactive ProteinAleksandra Urban0Daria Kowalska1Grzegorz Stasiłojć2Alicja Kuźniewska3Anna Skrobińska4Emilia Arjona5Eugenia Castellote Alonso6María Ángeles Fenollosa Segarra7Ilse Jongerius8Ilse Jongerius9Robbert Spaapen10Simon Satchell11Marcel Thiel12Stanisław Ołdziej13Santiago Rodriguez de Córdoba14Marcin Okrój15Department of Cell Biology and Immunology, Intercollegiate Faculty of Biotechnology of University of Gdańsk and Medical University of Gdańsk, Gdańsk, PolandDepartment of Cell Biology and Immunology, Intercollegiate Faculty of Biotechnology of University of Gdańsk and Medical University of Gdańsk, Gdańsk, PolandDepartment of Cell Biology and Immunology, Intercollegiate Faculty of Biotechnology of University of Gdańsk and Medical University of Gdańsk, Gdańsk, PolandDepartment of Cell Biology and Immunology, Intercollegiate Faculty of Biotechnology of University of Gdańsk and Medical University of Gdańsk, Gdańsk, PolandDepartment of Cell Biology and Immunology, Intercollegiate Faculty of Biotechnology of University of Gdańsk and Medical University of Gdańsk, Gdańsk, PolandCentro de Investigaciones Biológicas and Centro de Investigación Biomédica en Enfermedades Raras, Madrid, SpainServicio Nefrología, Consorci Hospitaliri de Vic, Barcelona, SpainServicio de Nefrología, Hospital General Universitario de Castellón, Castellón, SpainDepartment of Immunopathology, Sanquin Research, Amsterdam and Landsteiner Laboratory, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, NetherlandsEmma Children’s Hospital, Department of Pediatric Immunology, Rheumatology and Infectious Diseases, Amsterdam University Medical Center, Amsterdam, NetherlandsDepartment of Immunopathology, Sanquin Research, Amsterdam and Landsteiner Laboratory, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, NetherlandsBristol Renal, Bristol Medical School, University of Bristol, Bristol, United KingdomLaboratory of Biopolymers Structure, Intercollegiate Faculty of Biotechnology of University of Gdańsk and Medical University of Gdańsk, Gdańsk, PolandLaboratory of Biopolymers Structure, Intercollegiate Faculty of Biotechnology of University of Gdańsk and Medical University of Gdańsk, Gdańsk, PolandCentro de Investigaciones Biológicas and Centro de Investigación Biomédica en Enfermedades Raras, Madrid, SpainDepartment of Cell Biology and Immunology, Intercollegiate Faculty of Biotechnology of University of Gdańsk and Medical University of Gdańsk, Gdańsk, PolandThe 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.https://www.frontiersin.org/articles/10.3389/fimmu.2021.724361/fullcomplement systemaHUSC3 glomerulopathycomplement C2endothelial cells |
| spellingShingle | Aleksandra Urban Daria Kowalska Grzegorz Stasiłojć Alicja Kuźniewska Anna Skrobińska Emilia Arjona Eugenia Castellote Alonso María Ángeles Fenollosa Segarra Ilse Jongerius Ilse Jongerius Robbert Spaapen Simon Satchell Marcel Thiel Stanisław Ołdziej Santiago Rodriguez de Córdoba Marcin Okrój Gain-of-Function Mutations R249C and S250C in Complement C2 Protein Increase C3 Deposition in the Presence of C-Reactive Protein Frontiers in Immunology complement system aHUS C3 glomerulopathy complement C2 endothelial cells |
| 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 | complement system aHUS C3 glomerulopathy complement C2 endothelial cells |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2021.724361/full |
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