Gain-of-function mutations R249C and S250C in complement C2 protein increase C3 deposition in the presence of C-reactive protein

8 p.-4 fig.

Detalhes bibliográficos
Autores: Urban, Aleksandra, Kowalska, Daria, Stasiłojć, Grzegorz, Kuźniewska, Alicja, Skrobi´nska, Anna, Arjona, Emilia, Castellote Alonso, Eugenia, Fenollosa, María Ángeles, Jongerius, Ilse, Spaapen, Robbert, Satchell, Simon, Thiel, Marcel, Oldziej, Stanislaw, Rodríguez de Córdoba, Santiago, Okrój, Marcin
Formato: artículo
Estado:Versión publicada
Fecha de publicación:2021
País:España
Recursos:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/261212
Acesso em linha:http://hdl.handle.net/10261/261212
Access Level:acceso abierto
Palavra-chave:Complement system
aHUS
C3 glomerulopathy
Complement C2
Endothelial cells
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spelling Gain-of-function mutations R249C and S250C in complement C2 protein increase C3 deposition in the presence of C-reactive proteinUrban, AleksandraKowalska, DariaStasiłojć, GrzegorzKuźniewska, AlicjaSkrobi´nska, AnnaArjona, EmiliaCastellote Alonso, EugeniaFenollosa, María ÁngelesJongerius, IlseSpaapen, RobbertSatchell, SimonThiel, MarcelOldziej, StanislawRodríguez de Córdoba, SantiagoOkrój, MarcinComplement systemaHUSC3 glomerulopathyComplement C2Endothelial cells8 p.-4 fig.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.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 Economía y Competitividad-FEDER (PID2019-104912RB-I00) and Autonomous Region of Madrid (S2017/BMD-3673).Peer reviewedFrontiers MediaNational Science Centre (Poland)Ministerio de Economía y Competitividad (España)European CommissionComunidad de MadridUrban, Aleksandra [0000-0002-7299-4935]Kowalska, Daria [0000-0002-2427-8221]Stasiłojć, Grzegorz [0000-0002-4158-1935]Kuźniewska, Alicja [0000-0002-8055-1835]Arjona, Emilia [0000-0002-0753-3657]Jongerius, Ilse [0000-0002-7759-9897]Spaapen, Robbert [0000-0002-1329-8606]Satchell, Simon [0000-0001-5276-4537]Thiel, Marcel [0000-0002-6403-9436]Oldziej, Stanislaw [0000-0002-4583-3941]Rodríguez de Córdoba, Santiago [0000-0001-6401-1874]Okrój, Marcin [0000-0003-2935-2301]Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]202220222021info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Publisher's versioninfo:eu-repo/semantics/publishedVersionhttp://hdl.handle.net/10261/261212reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Inglés#PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE#info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/PID2019-104912RB-I00S2017/BMD-3673/COMPLEMENTO II CMhttps://doi.org/10.3389/fimmu.2021.724361Síinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/2612122026-05-22T06:33:51Z
dc.title.none.fl_str_mv 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
spellingShingle Gain-of-function mutations R249C and S250C in complement C2 protein increase C3 deposition in the presence of C-reactive protein
Urban, Aleksandra
Complement system
aHUS
C3 glomerulopathy
Complement C2
Endothelial cells
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
dc.creator.none.fl_str_mv Urban, Aleksandra
Kowalska, Daria
Stasiłojć, Grzegorz
Kuźniewska, Alicja
Skrobi´nska, Anna
Arjona, Emilia
Castellote Alonso, Eugenia
Fenollosa, María Ángeles
Jongerius, Ilse
Spaapen, Robbert
Satchell, Simon
Thiel, Marcel
Oldziej, Stanislaw
Rodríguez de Córdoba, Santiago
Okrój, Marcin
author Urban, Aleksandra
author_facet Urban, Aleksandra
Kowalska, Daria
Stasiłojć, Grzegorz
Kuźniewska, Alicja
Skrobi´nska, Anna
Arjona, Emilia
Castellote Alonso, Eugenia
Fenollosa, María Ángeles
Jongerius, Ilse
Spaapen, Robbert
Satchell, Simon
Thiel, Marcel
Oldziej, Stanislaw
Rodríguez de Córdoba, Santiago
Okrój, Marcin
author_role author
author2 Kowalska, Daria
Stasiłojć, Grzegorz
Kuźniewska, Alicja
Skrobi´nska, Anna
Arjona, Emilia
Castellote Alonso, Eugenia
Fenollosa, María Ángeles
Jongerius, Ilse
Spaapen, Robbert
Satchell, Simon
Thiel, Marcel
Oldziej, Stanislaw
Rodríguez de Córdoba, Santiago
Okrój, Marcin
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv National Science Centre (Poland)
Ministerio de Economía y Competitividad (España)
European Commission
Comunidad de Madrid
Urban, Aleksandra [0000-0002-7299-4935]
Kowalska, Daria [0000-0002-2427-8221]
Stasiłojć, Grzegorz [0000-0002-4158-1935]
Kuźniewska, Alicja [0000-0002-8055-1835]
Arjona, Emilia [0000-0002-0753-3657]
Jongerius, Ilse [0000-0002-7759-9897]
Spaapen, Robbert [0000-0002-1329-8606]
Satchell, Simon [0000-0001-5276-4537]
Thiel, Marcel [0000-0002-6403-9436]
Oldziej, Stanislaw [0000-0002-4583-3941]
Rodríguez de Córdoba, Santiago [0000-0001-6401-1874]
Okrój, Marcin [0000-0003-2935-2301]
Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
dc.subject.none.fl_str_mv Complement system
aHUS
C3 glomerulopathy
Complement C2
Endothelial cells
topic Complement system
aHUS
C3 glomerulopathy
Complement C2
Endothelial cells
description 8 p.-4 fig.
publishDate 2021
dc.date.none.fl_str_mv 2021
2022
2022
dc.type.none.fl_str_mv info:eu-repo/semantics/article
http://purl.org/coar/resource_type/c_6501
Publisher's version
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10261/261212
url http://hdl.handle.net/10261/261212
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv #PLACEHOLDER_PARENT_METADATA_VALUE#
#PLACEHOLDER_PARENT_METADATA_VALUE#
info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/PID2019-104912RB-I00
S2017/BMD-3673/COMPLEMENTO II CM
https://doi.org/10.3389/fimmu.2021.724361
Sí
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv Frontiers Media
publisher.none.fl_str_mv Frontiers Media
dc.source.none.fl_str_mv reponame:DIGITAL.CSIC. Repositorio Institucional del CSIC
instname:Consejo Superior de Investigaciones Científicas (CSIC)
instname_str Consejo Superior de Investigaciones Científicas (CSIC)
reponame_str DIGITAL.CSIC. Repositorio Institucional del CSIC
collection DIGITAL.CSIC. Repositorio Institucional del CSIC
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15.198674

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