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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Bibliographic Details
Published in:	Frontiers in immunology 2021-11, Vol.12, p.724361-724361
Main Authors:	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
Format:	Article
Language:	eng
Subjects:	aHUS C-Reactive Protein - metabolism C3 glomerulopathy complement C2 Complement C2 - genetics Complement C3 - metabolism complement system endothelial cells Gain of Function Mutation Humans Immunology Kidney Diseases - genetics Kidney Diseases - metabolism
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Summary:	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.
ISSN:	1664-3224 1664-3224