2015
DOI: 10.1016/j.molimm.2015.03.248
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The molecular and structural bases for the association of complement C3 mutations with atypical hemolytic uremic syndrome

Abstract: HighlightsMutations in C3 have been associated with aHUS and other glomerulopathies.aHUS-associated C3 mutants R592W, R161W, and I1157T impair regulation by MCP, but not by FH.EM analysis provides the structural basis for the functional impairment of the R161W and I1157T mutants.Data supports aHUS-associated C3 mutations selectively affect complement regulation on surfaces.

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Cited by 52 publications
(60 citation statements)
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“…2 a). Mutations in C3 reportedly account for the increased complement activation on platelets and glomerular endothelium [30,31] and the etiology of 2-10% of the aHUS patients [1] . In this study, Chinese aHUS patients carried 4 different missense mutations in C3.…”
Section: Discussionmentioning
confidence: 99%
“…2 a). Mutations in C3 reportedly account for the increased complement activation on platelets and glomerular endothelium [30,31] and the etiology of 2-10% of the aHUS patients [1] . In this study, Chinese aHUS patients carried 4 different missense mutations in C3.…”
Section: Discussionmentioning
confidence: 99%
“…Mapping of these critical residues of CCP2 and CCP3 onto the modeled structure of the C3b-Kaposica complex depicts that CCP2 residues do not participate in C3b contacts, whereas CCP3 residues bridge the MG2 and CUB domains of C3b. It should be pointed out here that there exists a significant flexibility between the core of C3b (MG ring) and CUB/thioester-containing domain (TED) (26)(27)(28). We, therefore, propose that the bridge formed by CCP3 of Kaposica between MG2 and CUB holds the latter in a proper orientation relative to the core of C3b, which then allows its efficient cleavage by factor I.…”
Section: Discussionmentioning
confidence: 99%
“…These data, together with current structural data of C3b and its complexes with complement regulators, are providing a framework to predict the functional consequences of the C3 genetic variants found in patients (Schramm et al, 2015;Martínez-Barricarte et al, 2015). This should aid molecular diagnostics and even guide therapeutic decisions.…”
Section: Gain Of Function Mutations In C3mentioning
confidence: 96%
“…Two of these gain-of-function C3 mutations, C3-R161W and C3-I1157T, are relatively prevalent mutations representing around 50% of the aHUS patients carrying C3 mutations in Europe and Japan, respectively (Roumenina et al, 2012;Volokhina et al, 2012;Matsumoto et al, 2014). Detailed functional analysis of these prevalent mutations, using both recombinant and plasma-purified proteins demonstrated impaired regulation by MCP, with normal or slightly impaired FH cofactor activity (Schramm et al, 2015;Roumenina et al, 2012;Frémeaux-Bacchi et al, 2008;Martínez-Barricarte et al, 2015). In contrast, the single DDD-associated C3 mutation characterized thus far (C3-del923DG) presented altered sensitivity of C3b to inactivation by FH (or CR1) and normal susceptibility to MCP cofactor activity and accelerated decay by DAF (Martínez-Barricarte et al, 2010).…”
Section: Gain Of Function Mutations In C3mentioning
confidence: 99%