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Article: Aprevalent C3 mutation in aHUS patients causes a direct C3 convertase gain offunction

TitleAprevalent C3 mutation in aHUS patients causes a direct C3 convertase gain offunction
Authors
Issue Date2012
Citation
Blood, 2012, v. 119 n. 18, p. 4182-4191 How to Cite?
AbstractAtypical hemolytic uremic syndrome (aHUS) is a rare renal thrombotic microangiopathy commonly associated with rare genetic variants in complement system genes, unique to each patient/family. Here, we report 14 sporadic aHUS patients carrying the same mutation, R139W, in the complement C3 gene. The clinical presentation was with a rapid progression to end-stage renal disease (6 of 14) and an unusually high frequency of cardiac (8 of 14) and/or neurologic (5 of 14) events. Although resting glomerular endothelial cells (GEnCs) remained unaffected by R139W-C3 sera, the incubation of those sera with GEnC preactivated with proinflammatory stimuli led to increased C3 deposition, C5a release, and procoagulant tissue-factor expression. This functional consequence of R139W-C3 resulted from the formation of a hyperactive C3 convertase. Mutant C3 showed an increased affinity for factor B and a reduced binding to membrane cofactor protein (MCP; CD46), but a normal regulation by factor H (FH). In addition, the frequency of at-risk FH and MCP haplotypes was significantly higher in the R139WaHUS patients, compared with normal donors or to healthy carriers. These genetic background differences could explain the R139W-aHUS incomplete penetrance. These results demonstrate that this C3 mutation, especially when associated with an at-risk FH and/or MCP haplotypes, becomes pathogenic following an inflammatory endothelium-damaging event. © 2012 by The American Society of Hematology.
Persistent Identifierhttp://hdl.handle.net/10722/195510
ISSN
2015 Impact Factor: 11.841
2015 SCImago Journal Rankings: 6.395
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorRoumenina, LT-
dc.contributor.authorFrimat, M-
dc.contributor.authorMiller, EC-
dc.contributor.authorProvot, F-
dc.contributor.authorDragon-Durey, MA-
dc.contributor.authorBordereau, P-
dc.contributor.authorBigot, S-
dc.contributor.authorHue, C-
dc.contributor.authorSatchell, SC-
dc.contributor.authorMathieson, PW-
dc.contributor.authorMousson, C-
dc.contributor.authorNoe, C-
dc.contributor.authorSautes-Fridman, C-
dc.contributor.authorHalbwachs-Mecarelli, L-
dc.contributor.authorAtkinson, JP-
dc.contributor.authorLionet, A-
dc.contributor.authorFremeaux-Bacchi, V-
dc.date.accessioned2014-02-28T06:12:15Z-
dc.date.available2014-02-28T06:12:15Z-
dc.date.issued2012-
dc.identifier.citationBlood, 2012, v. 119 n. 18, p. 4182-4191-
dc.identifier.issn0006-4971-
dc.identifier.urihttp://hdl.handle.net/10722/195510-
dc.description.abstractAtypical hemolytic uremic syndrome (aHUS) is a rare renal thrombotic microangiopathy commonly associated with rare genetic variants in complement system genes, unique to each patient/family. Here, we report 14 sporadic aHUS patients carrying the same mutation, R139W, in the complement C3 gene. The clinical presentation was with a rapid progression to end-stage renal disease (6 of 14) and an unusually high frequency of cardiac (8 of 14) and/or neurologic (5 of 14) events. Although resting glomerular endothelial cells (GEnCs) remained unaffected by R139W-C3 sera, the incubation of those sera with GEnC preactivated with proinflammatory stimuli led to increased C3 deposition, C5a release, and procoagulant tissue-factor expression. This functional consequence of R139W-C3 resulted from the formation of a hyperactive C3 convertase. Mutant C3 showed an increased affinity for factor B and a reduced binding to membrane cofactor protein (MCP; CD46), but a normal regulation by factor H (FH). In addition, the frequency of at-risk FH and MCP haplotypes was significantly higher in the R139WaHUS patients, compared with normal donors or to healthy carriers. These genetic background differences could explain the R139W-aHUS incomplete penetrance. These results demonstrate that this C3 mutation, especially when associated with an at-risk FH and/or MCP haplotypes, becomes pathogenic following an inflammatory endothelium-damaging event. © 2012 by The American Society of Hematology.-
dc.languageeng-
dc.relation.ispartofBlood-
dc.titleAprevalent C3 mutation in aHUS patients causes a direct C3 convertase gain offunction-
dc.typeArticle-
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1182/blood-2011-10-383281-
dc.identifier.pmid22246034-
dc.identifier.scopuseid_2-s2.0-84860711841-
dc.identifier.volume119-
dc.identifier.issue18-
dc.identifier.spage4182-
dc.identifier.epage4191-
dc.identifier.isiWOS:000305284600015-

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