Journal article
Mapping interactions between complement C3 and regulators using mutations in atypical hemolytic uremic syndrome
Blood, Vol.125(15), pp.2359-2369
04/09/2015
DOI: 10.1182/blood-2014-10-609073
PMCID: PMC4392009
PMID: 25608561
Abstract
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.
Details
- Title: Subtitle
- Mapping interactions between complement C3 and regulators using mutations in atypical hemolytic uremic syndrome
- Creators
- Elizabeth C Schramm - Division of Rheumatology, Department of Medicine, Washington University School of Medicine, Saint Louis, MOLubka T Roumenina - INSERM UMRS 1138, Cordeliers Research Center, Paris, France; Université Paris Descartes Sorbonne Paris-Cité, Paris, France; Université Pierre et Marie Curie, Paris, FranceTania Rybkine - INSERM UMRS 1138, Cordeliers Research Center, Paris, France; Université Paris Descartes Sorbonne Paris-Cité, Paris, France; Université Pierre et Marie Curie, Paris, FranceSophie Chauvet - INSERM UMRS 1138, Cordeliers Research Center, Paris, France; Université Paris Descartes Sorbonne Paris-Cité, Paris, France; Université Pierre et Marie Curie, Paris, FrancePaula Vieira-Martins - INSERM UMRS 1138, Cordeliers Research Center, Paris, FranceChristophe Hue - INSERM UMRS 1138, Cordeliers Research Center, Paris, France; Université Paris Descartes Sorbonne Paris-Cité, Paris, France; Université Pierre et Marie Curie, Paris, FranceTara Maga - Molecular Otolaryngology and Renal Research Laboratories, and Rare Renal Disease Clinic, Departments of Pediatrics and Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IAElisabetta Valoti - Laboratory of Immunology and Genetics of Transplantation and Rare Diseases, Mario Negri Institute for Pharmacological Research, Ranica Bergamo, ItalyValerie Wilson - Northern Molecular Genetics Service, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, United KingdomSakari Jokiranta - Department of Bacteriology and Immunology, Medicum, and Research Programs Unit, Immunobiology, University of Helsinki and Helsinki University Hospital, Helsinki, FinlandRichard J H Smith - Molecular Otolaryngology and Renal Research Laboratories, and Rare Renal Disease Clinic, Departments of Pediatrics and Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IAMarina Noris - Laboratory of Immunology and Genetics of Transplantation and Rare Diseases, Mario Negri Institute for Pharmacological Research, Ranica Bergamo, ItalyTim Goodship - Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom; andJohn P Atkinson - Division of Rheumatology, Department of Medicine, Washington University School of Medicine, Saint Louis, MOVeronique Fremeaux-Bacchi - INSERM UMRS 1138, Cordeliers Research Center, Paris, France; Université Paris Descartes Sorbonne Paris-Cité, Paris, France; Université Pierre et Marie Curie, Paris, France; Assistance Publique-Hôpitaux de Paris, Service d'Immunologie Biologique, Hôpital Européen Georges Pompidou, Paris, France
- Resource Type
- Journal article
- Publication Details
- Blood, Vol.125(15), pp.2359-2369
- DOI
- 10.1182/blood-2014-10-609073
- PMID
- 25608561
- PMCID
- PMC4392009
- NLM abbreviation
- Blood
- ISSN
- 1528-0020
- eISSN
- 1528-0020
- Publisher
- United States
- Grant note
- RC2 HL103010 / NHLBI NIH HHS HL-102923 / NHLBI NIH HHS T32 GM008629 / NIGMS NIH HHS G0701325 / Medical Research Council U54 HL112303 / NHLBI NIH HHS RC2 HL102924 / NHLBI NIH HHS U54-HL112303 / NHLBI NIH HHS UC2 HL102926 / NHLBI NIH HHS RC2 HL102923 / NHLBI NIH HHS RC2 HL102926 / NHLBI NIH HHS UC2 HL103010 / NHLBI NIH HHS UC2 HL102925 / NHLBI NIH HHS HL-102925 / NHLBI NIH HHS HL 102924 / NHLBI NIH HHS UC2 HL102924 / NHLBI NIH HHS HL 103010 / NHLBI NIH HHS HL-102926 / NHLBI NIH HHS R01-AIO41592 / PHS HHS UC2 HL102923 / NHLBI NIH HHS RC2 HL102925 / NHLBI NIH HHS
- Language
- English
- Date published
- 04/09/2015
- Academic Unit
- Roy J. Carver Department of Biomedical Engineering; Molecular Physiology and Biophysics; Anatomy and Cell Biology; Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Otolaryngology; Internal Medicine
- Record Identifier
- 9984006491002771
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