Journal article
Complement factor B mutations in atypical hemolytic uremic syndrome-disease-relevant or benign?
Journal of the American Society of Nephrology, Vol.25(9), pp.2053-2065
09/2014
DOI: 10.1681/asn.2013070796
PMCID: PMC4147975
PMID: 24652797
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.
Details
- Title: Subtitle
- Complement factor B mutations in atypical hemolytic uremic syndrome-disease-relevant or benign?
- Creators
- Maria Chiara Marinozzi - 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, FranceLaura Vergoz - 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, FranceTania Rybkine - 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, FranceStephanie Ngo - Assistance Publique-Hôpitaux de Paris, Service d'Immunologie Biologique, Hôpital Européen Georges Pompidou, Paris, FranceSerena Bettoni - IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Clinical Research Center for Rare Diseases Aldo e Cele Daccò, Ranica, Bergamo, ItalyAnastas Pashov - Molecular Medicine, Stephan Angelov Institute of Microbiology, Bulgarian Academy of Sciences, Sofia, BulgariaMathieu Cayla - 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, FranceFanny Tabarin - 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, FranceMathieu Jablonski - 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, FranceChristophe Hue - 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, FranceRichard J 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, Iowa; andMarina Noris - Laboratory of Immunology and Genetics of Transplantation and Rare Diseases, Mario Negri Institute for Pharmacological Research, Ranica, Bergamo, ItalyLise Halbwachs-Mecarelli - 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, FranceRoberta Donadelli - IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Clinical Research Center for Rare Diseases Aldo e Cele Daccò, Ranica, Bergamo, ItalyVeronique Fremeaux-Bacchi - 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, FranceLubka T Roumenina - 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
- Resource Type
- Journal article
- Publication Details
- Journal of the American Society of Nephrology, Vol.25(9), pp.2053-2065
- DOI
- 10.1681/asn.2013070796
- PMID
- 24652797
- PMCID
- PMC4147975
- NLM abbreviation
- J Am Soc Nephrol
- ISSN
- 1533-3450
- eISSN
- 1533-3450
- Publisher
- United States
- Grant note
- GGP09075 / Telethon
- Language
- English
- Date published
- 09/2014
- 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
- 9984006354402771
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