Journal
BLOOD
Volume 125, Issue 15, Pages 2359-2369Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2014-10-609073
Keywords
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Funding
- Lung GO Sequencing Project [HL-102923]
- Women's Health Initiative Sequencing Project [HL-102924]
- Broad GO Sequencing Project [HL-102925]
- Seattle GO Sequencing Project [HL-102926]
- Heart GO Sequencing Project [HL-103010]
- Agence Nationale de la Recherche (ANR Genopath) [09geno03101I]
- Assistance Publique-Hopitaux de Paris (Programme Hospitalier de Recherche Clinique) [AOM08198]
- European Union [2012-305608]
- Association for Information and Research on Genetic Renal Diseases (AIRG) France
- Institut national de la sante et de la recherche medicale
- European Molecular Biology Organization (EMBO) Long Term Fellowship [ALTF 444-2007]
- Associazione Ricerca Trapianti Fondazione Onlus (Milan, Italy)
- National Institutes of Health, Allergy and Infectious Diseases [R01-AIO41592]
- National Heart, Lung, and Blood Institute [U54-HL112303]
- UK Medical Research Council [G0701325]
- Academy of Finland [255922, 259793]
- Sigrid Juselius Foundation
- Medical Research Council [G0701325] Funding Source: researchfish
- MRC [G0701325] Funding Source: UKRI
- Academy of Finland (AKA) [255922] Funding Source: Academy of Finland (AKA)
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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.
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