Complement factor B mutations in atypical hemolytic uremic syndrome-disease-relevant or benign?

Maria Chiara Marinozzi, Laura Vergoz, Tania Rybkine, Stephanie Ngo, Serena Bettoni, Anastas Pashov, Mathieu Cayla, Fanny Tabarin, Mathieu Jablonski, Christophe Hue, Richard J Smith, Marina Noris, Lise Halbwachs-Mecarelli, Roberta Donadelli, Veronique Fremeaux-Bacchi, Lubka T Roumenina

Journal: Journal of the American Society of Nephrology : JASN 2014;25(9):2053-65

PMID: 24652797

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Abstract

Atypical hemolytic uremic syndrome (aHUS) is a genetic ultrarare renal disease associated with overactivation of the alternative pathway of complement. Four gain-of-function mutations that form a hyperactive or deregulated C3 convertase have been identified in Factor B (FB) ligand binding sites. Here, we studied the functional consequences of 10 FB genetic changes recently identified from different aHUS cohorts. Using several tests for alternative C3 and C5 convertase formation and regulation, we identified two gain-of-function and potentially disease-relevant mutations that formed either an overactive convertase (M433I) or a convertase resistant to decay by FH (K298Q). One mutation (R178Q) produced a partially cleaved protein with no ligand binding or functional activity. Seven genetic changes led to near-normal or only slightly reduced ligand binding and functional activity compared with the most common polymorphism at position 7, R7. Notably, none of the algorithms used to predict the disease relevance of FB mutations agreed completely with the experimental data, suggesting that in silico approaches should be undertaken with caution. These data, combined with previously published results, suggest that 9 of 15 FB genetic changes identified in patients with aHUS are unrelated to disease pathogenesis. This study highlights that functional assessment of identified nucleotide changes in FB is mandatory to confirm disease association.

Address: Institut National de la Santé et de la Recherche Médicale UMRS 1138, Cordeliers Research Center, Complement and Diseases Team, Paris, France; Université Paris Descartes Sorbonne Paris-Cité, Paris, France; Assistance Publique-Hôpitaux de Paris, Service d'Immunologie Biologique, Hôpital Européen Georges Pompidou, Paris, France;; Institut National de la Santé et de la Recherche Médicale UMRS 1138, Cordeliers Research Center, Complement and Diseases Team, Paris, France; Université Paris Descartes Sorbonne Paris-Cité, Paris, France; Université Pierre et Marie Curie (Paris-6), Paris, France;; Assistance Publique-Hôpitaux de Paris, Service d'Immunologie Biologique, Hôpital Européen Georges Pompidou, Paris, France;; IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Clinical Research Center for Rare Diseases Aldo e Cele Daccò, Ranica, Bergamo, Italy;; Molecular Medicine, Stephan Angelov Institute of Microbiology, Bulgarian Academy of Sciences, Sofia, Bulgaria;; 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, Iowa; and.; Laboratory of Immunology and Genetics of Transplantation and Rare Diseases, Mario Negri Institute for Pharmacological Research, Ranica, Bergamo, Italy.; Institut National de la Santé et de la Recherche Médicale UMRS 1138, Cordeliers Research Center, Complement and Diseases Team, Paris, France; Assistance Publique-Hôpitaux de Paris, Service d'Immunologie Biologique, Hôpital Européen Georges Pompidou, Paris, France;; Institut National de la Santé et de la Recherche Médicale UMRS 1138, Cordeliers Research Center, Complement and Diseases Team, Paris, France; Université Paris Descartes Sorbonne Paris-Cité, Paris, France; Université Pierre et Marie Curie (Paris-6), Paris, France; [email protected].

DOI: 10.1681/ASN.2013070796

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MeSH Terms: Amino Acid Substitution, Atypical Hemolytic Uremic Syndrome, Binding Sites, Complement C3 Convertase, Alternative Pathway, Complement C3b, Complement C5 Convertase, Alternative Pathway, Complement Factor B, Complement Pathway, Alternative, Computer Simulation, Gene Frequency, Human Umbilical Vein Endothelial Cells, Humans, Ligands, Models, Molecular, Multiprotein Complexes, Mutation, Polymorphism, Genetic, Recombinant Proteins