title: Complement factor B mutations in atypical hemolytic uremic syndrome-disease-relevant or benign?
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.
authors.affiliation: 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;
authors.forename: Maria Chiara
authors.initials: MC
authors.lastname: Marinozzi
authors.affiliation: 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;
authors.forename: Laura
authors.initials: L
authors.lastname: Vergoz
authors.affiliation: 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;
authors.forename: Tania
authors.initials: T
authors.lastname: Rybkine
authors.affiliation: Assistance Publique-Hôpitaux de Paris, Service d'Immunologie Biologique, Hôpital Européen Georges Pompidou, Paris, France;
authors.forename: Stephanie
authors.initials: S
authors.lastname: Ngo
authors.affiliation: IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Clinical Research Center for Rare Diseases Aldo e Cele Daccò, Ranica, Bergamo, Italy;
authors.forename: Serena
authors.initials: S
authors.lastname: Bettoni
authors.affiliation: Molecular Medicine, Stephan Angelov Institute of Microbiology, Bulgarian Academy of Sciences, Sofia, Bulgaria;
authors.forename: Anastas
authors.initials: A
authors.lastname: Pashov
authors.affiliation: 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;
authors.forename: Mathieu
authors.initials: M
authors.lastname: Cayla
authors.affiliation: 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;
authors.forename: Fanny
authors.initials: F
authors.lastname: Tabarin
authors.affiliation: 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;
authors.forename: Mathieu
authors.initials: M
authors.lastname: Jablonski
authors.affiliation: 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;
authors.forename: Christophe
authors.initials: C
authors.lastname: Hue
authors.affiliation: 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.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Smith
authors.affiliation: Laboratory of Immunology and Genetics of Transplantation and Rare Diseases, Mario Negri Institute for Pharmacological Research, Ranica, Bergamo, Italy.
authors.forename: Marina
authors.initials: M
authors.lastname: Noris
authors.affiliation: 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;
authors.forename: Lise
authors.initials: L
authors.lastname: Halbwachs-Mecarelli
authors.affiliation: IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Clinical Research Center for Rare Diseases Aldo e Cele Daccò, Ranica, Bergamo, Italy;
authors.forename: Roberta
authors.initials: R
authors.lastname: Donadelli
authors.affiliation: 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;
authors.forename: Veronique
authors.initials: V
authors.lastname: Fremeaux-Bacchi
authors.affiliation: 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; lubka.roumenina@crc.jussieu.fr.
authors.forename: Lubka T
authors.initials: LT
authors.lastname: Roumenina
mesh_terms: D019943:Amino Acid Substitution; D065766:Atypical Hemolytic Uremic Syndrome / Q000235:genetics* / Q000276:immunology*; D001665:Binding Sites / Q000235:genetics; D051561:Complement C3 Convertase, Alternative Pathway / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D003179:Complement C3b / Q000378:metabolism; D051566:Complement C5 Convertase, Alternative Pathway / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D011415:Complement Factor B / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D003170:Complement Pathway, Alternative / Q000235:genetics; D003198:Computer Simulation; D005787:Gene Frequency; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D046912:Multiprotein Complexes / Q000737:chemistry; D009154:Mutation; D011110:Polymorphism, Genetic; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism
chemical_list: D008024:Ligands; D046912:Multiprotein Complexes; D011994:Recombinant Proteins; D003179:Complement C3b; D051561:Complement C3 Convertase, Alternative Pathway; D051566:Complement C5 Convertase, Alternative Pathway; D011415:Complement Factor B