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Mapping interactions between complement C3 and regulators using mutations in atypical hemolytic uremic syndrome

Lookup NU author(s): Dr Valerie Wilson, Professor Tim Goodship, Dr Veronique Fremaux-Bacchi


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The pathogenesis of atypical hemolytic uremic syndrome (aHUS) is strongly linked to dysregulation of the alternative pathway of the complement system. Mutations in complement genes have been identified in about two-thirds of cases, with 5% to 15% being in C3. In this study, 23 aHUS-associated genetic changes in C3 were characterized relative to their interaction with the control proteins factor H (FH), membrane cofactor protein (MCP; CD46), and complement receptor 1 (CR1; CD35). In surface plasmon resonance experiments, 17 mutant recombinant proteins demonstrated a defect in binding to FH and/or MCP, whereas 2 demonstrated reduced binding to CR1. In the majority of cases, decreased binding affinity translated to a decrease in proteolytic inactivation (known as cofactor activity) of C3b via FH and MCP. These results were used to map the putative binding regions of C3b involved in the interaction with MCP and CR1 and interrogated relative to known FH binding sites. Seventy-six percent of patients with C3 mutations had low C3 levels that correlated with disease severity. This study expands our knowledge of the functional consequences of aHUS-associated C3 mutations relative to the interaction of C3 with complement regulatory proteins mediating cofactor activity.

Publication metadata

Author(s): Schramm EC, Roumenina LT, Rybkine T, Chauvet S, Vieira-Martins P, Hue C, Maga T, Valoti E, Wilson V, Jokiranta S, Smith RJH, Noris M, Goodship T, Atkinson JP, Fremeaux-Bacchi V

Publication type: Article

Publication status: Published

Journal: Blood

Year: 2015

Volume: 125

Issue: 15

Pages: 2359-2369

Print publication date: 09/04/2015

Online publication date: 21/01/2015

Acceptance date: 07/01/2015

ISSN (print): 0006-4971

ISSN (electronic): 1528-0020

Publisher: American Society of Hematology


DOI: 10.1182/blood-2014-10-609073


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Funder referenceFunder name
Institut national de la sante et de la recherche medicale
Association for Information and Research on Genetic Renal Diseases (AIRG) France
Associazione Ricerca Trapianti Fondazione Onlus (Milan, Italy)
Sigrid Juselius Foundation
2012-305608European Union
09geno03101IAgence Nationale de la Recherche (ANR Genopath)
255922Academy of Finland
ALTF 444-2007European Molecular Biology Organization (EMBO) Long Term Fellowship
AOM08198Assistance Publique-Hopitaux de Paris (Programme Hospitalier de Recherche Clinique)
259793Academy of Finland
G0701325UK Medical Research Council
HL-102925Broad GO Sequencing Project
HL-102923Lung GO Sequencing Project
HL-102924Women's Health Initiative Sequencing Project
HL-102926Seattle GO Sequencing Project
HL-103010Heart GO Sequencing Project
R01-AIO41592National Institutes of Health, Allergy and Infectious Diseases
U54-HL112303National Heart, Lung, and Blood Institute