@article{f4ce545ef2cf4ed3af4cc0d8443f2af9,
title = "Gain-of-Function Mutations R249C and S250C in Complement C2 Protein Increase C3 Deposition in the Presence of C-Reactive Protein",
abstract = "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.",
keywords = "C3 glomerulopathy, aHUS, complement C2, complement system, endothelial cells",
author = "Aleksandra Urban and Daria Kowalska and Grzegorz Stasi{\l}oj{\'c} and Alicja Ku{\'z}niewska and Anna Skrobi{\'n}ska and Emilia Arjona and Alonso, {Eugenia Castellote} and {Fenollosa Segarra}, {Mar{\'i}a {\'A}ngeles} and Ilse Jongerius and Robbert Spaapen and Simon Satchell and Marcel Thiel and Stanis{\l}aw O{\l}dziej and {Rodriguez de C{\'o}rdoba}, Santiago and Marcin Okr{\'o}j",
note = "Funding Information: The project was funded by National Science Centre Poland grant nos. 2015/18/M/NZ6/00334 and 2018/29/N/NZ6/01413. SRC was supported by grants from the Spanish Ministerio de Economı{\'a} y Competitividad-FEDER (PID2019-104912RB-I00) and Autonomous Region of Madrid (S2017/BMD-3673). Computational resources used in this project were provided by the Informatics Center of the Metropolitan Academic Network (IC MAN-TASK) in Gda{\'n}sk. Funding Information: The project was funded by National Science Centre Poland grant nos. 2015/18/M/NZ6/00334 and 2018/29/N/NZ6/01413. SRC was supported by grants from the Spanish Ministerio de Econom?a y Competitividad-FEDER (PID2019-104912RB-I00) and Autonomous Region of Madrid (S2017/BMD-3673). Computational resources used in this project were provided by the Informatics Center of the Metropolitan Academic Network (IC MAN-TASK) in Gda?sk. Publisher Copyright: Copyright {\textcopyright} 2021 Urban, Kowalska, Stasi{\l}oj{\'c}, Ku{\'z}niewska, Skrobi{\'n}ska, Arjona, Alonso, Fenollosa Segarra, Jongerius, Spaapen, Satchell, Thiel, O{\l}dziej, Rodriguez de C{\'o}rdoba and Okr{\'o}j.",
year = "2021",
month = nov,
day = "25",
doi = "https://doi.org/10.3389/fimmu.2021.724361",
language = "English",
volume = "12",
journal = "Frontiers in immunology",
issn = "1664-3224",
publisher = "Frontiers Media S.A.",
}