The molecular and structural bases for the association of complement C3 mutations with atypical hemolytic uremic syndrome

Martı́nez-Barricarte, Rubén; Heurich, Meike; López-Perrote, Andrés; Tortajada, Agustín; Pinto, Sheila; López-Trascasa, Margarita; Sánchez-Corral, Pilar; Morgan, B. Paul; Llorca, Óscar; Harris, Claire L.; Córdoba, Santiago Rodrı́guez de

doi:10.1016/j.molimm.2015.03.248

Cited by 52 publications

(60 citation statements)

References 49 publications

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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%

Comprehensive Analysis of Complement Genes in Patients with Atypical Hemolytic Uremic Syndrome

Zhang

Liang

et al. 2016

Am J Nephrol

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Background: Genetic defects in complement proteins reportedly contribute to the atypical hemolytic uremic syndrome (aHUS). Numerous genetic studies have been published in recent years, but limited data have been gathered from Asian countries. Methods: Genetic variants of 11 complement genes were analyzed in 23 Chinese patients with aHUS by high-throughput sequencing. The genotype-phenotype relationship in the Han population was evaluated and compared with the relationship that existed in other ethnicities. Results: We identified 20 causative mutations in complement genes, including 19 missense mutations and 1 splicing mutation. Six previously reported mutations, 6 mutations detected for the first time, and 8 rare polymorphisms were noted. Twelve out of 23 patients harbored complement mutations. Among the patients, one was a homozygote (Arg142Cys in CFHR3), and 4 carried combined mutations. Chinese patients have a similar prevalence of complement mutations as European, Japanese, and American patients. Complement factor H (CFH) mutations were common in aHUS in different ethnicities, but Chinese patients exhibited a higher percentage of complement factor B mutations than were found in European patients and a lower percentage of component 3 (C3) mutations than in Japanese patients. Compared with non-carriers, the aHUS patients carrying mutations had reduced C3 levels. In particular, patients with CFH mutations had a worse renal function than those with membrane cofactor protein mutations, a higher level of serum creatinine at the disease onset and a higher percentage of renal insufficiency during follow-up. Conclusions: Because complement genetic dysfunction has clinical significance in aHUS, a comprehensive assessment of variants is necessary for the proper management of aHUS patients in China.

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Section: Discussionmentioning

confidence: 99%

Comprehensive Analysis of Complement Genes in Patients with Atypical Hemolytic Uremic Syndrome

Zhang

Liang

et al. 2016

Am J Nephrol

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“…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%

Mutational analysis of Kaposica reveals that bridging of MG2 and CUB domains of target protein is crucial for the cofactor activity of RCA proteins

Gautam

Panse

Ghosh

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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The complement system has evolved to annul pathogens, but its improper regulation is linked with diseases. Efficient regulation of the system is primarily provided by a family of proteins termed regulators of complement activation (RCA). The knowledge of precise structural determinants of RCA proteins critical for imparting the regulatory activities and the molecular events underlying the regulatory processes, nonetheless, is still limited. Here, we have dissected the structural requirements of RCA proteins that are crucial for one of their two regulatory activities, the cofactor activity (CFA), by using the Kaposi’s sarcoma-associated herpesvirus RCA homolog Kaposica as a model protein. We have scanned the entire Kaposica molecule by sequential mutagenesis using swapping and site-directed mutagenesis, which identified residues critical for its interaction with C3b and factor I. Mapping of these residues onto the modeled structure of C3b–Kaposica–factor I complex supported the mutagenesis data. Furthermore, the model suggested that the C3b-interacting residues bridge the CUB (complement C1r-C1s, Uegf, Bmp1) and MG2 (macroglobulin-2) domains of C3b. Thus, it seems that stabilization of the CUB domain with respect to the core of the C3b molecule is central for its CFA. Identification of CFA-critical regions in Kaposica guided experiments in which the equivalent regions of membrane cofactor protein were swapped into decay-accelerating factor. This strategy allowed CFA to be introduced into decay-accelerating factor, suggesting that viral and human regulators use a common mechanism for CFA.

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“…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%

Complement genetics and susceptibility to inflammatory disease. Lessons from genotype–phenotype correlations

Córdoba

2016

Immunobiology

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The molecular and structural bases for the association of complement C3 mutations with atypical hemolytic uremic syndrome

Cited by 52 publications

References 49 publications

Comprehensive Analysis of Complement Genes in Patients with Atypical Hemolytic Uremic Syndrome

Comprehensive Analysis of Complement Genes in Patients with Atypical Hemolytic Uremic Syndrome

Mutational analysis of Kaposica reveals that bridging of MG2 and CUB domains of target protein is crucial for the cofactor activity of RCA proteins

Complement genetics and susceptibility to inflammatory disease. Lessons from genotype–phenotype correlations

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