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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2021
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oai:doaj.org-article:717a2faa64dc496784006a113f6cb1362021-11-30T21:27:25ZGain-of-Function Mutations R249C and S250C in Complement C2 Protein Increase C3 Deposition in the Presence of C-Reactive Protein1664-322410.3389/fimmu.2021.724361https://doaj.org/article/717a2faa64dc496784006a113f6cb1362021-11-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fimmu.2021.724361/fullhttps://doaj.org/toc/1664-3224The 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.Aleksandra UrbanDaria KowalskaGrzegorz StasiłojćAlicja KuźniewskaAnna SkrobińskaEmilia ArjonaEugenia Castellote AlonsoMaría Ángeles Fenollosa SegarraIlse JongeriusIlse JongeriusRobbert SpaapenSimon SatchellMarcel ThielStanisław OłdziejSantiago Rodriguez de CórdobaMarcin OkrójFrontiers Media S.A.articlecomplement systemaHUSC3 glomerulopathycomplement C2endothelial cellsImmunologic diseases. AllergyRC581-607ENFrontiers in Immunology, Vol 12 (2021) |
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complement system aHUS C3 glomerulopathy complement C2 endothelial cells Immunologic diseases. Allergy RC581-607 |
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complement system aHUS C3 glomerulopathy complement C2 endothelial cells Immunologic diseases. Allergy RC581-607 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 |
| 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. |
| format |
article |
| 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 |
| title |
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_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_sort |
gain-of-function mutations r249c and s250c in complement c2 protein increase c3 deposition in the presence of c-reactive protein |
| publisher |
Frontiers Media S.A. |
| publishDate |
2021 |
| url |
https://doaj.org/article/717a2faa64dc496784006a113f6cb136 |
| work_keys_str_mv |
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