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: 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 (J Am Soc Nephrol) Vol. 25 Issue 9 Pg. 2053-65 (Sep 2014) ISSN: 1533-3450 [Electronic] United States
• PMID: 24652797 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 by the American Society of Nephrology.

Chemical References

• Ligands
• Multiprotein Complexes
• Recombinant Proteins
• Complement C3b
• Complement C3 Convertase, Alternative Pathway
• Complement C5 Convertase, Alternative Pathway
• Complement Factor B

Topics

• Amino Acid Substitution
• Atypical Hemolytic Uremic Syndrome (genetics, immunology)
• Binding Sites (genetics)
• Complement C3 Convertase, Alternative Pathway (chemistry, genetics, metabolism)
• Complement C3b (metabolism)
• Complement C5 Convertase, Alternative Pathway (chemistry, genetics, metabolism)
• Complement Factor B (chemistry, genetics, metabolism)
• Complement Pathway, Alternative (genetics)
• Computer Simulation
• Gene Frequency
• Human Umbilical Vein Endothelial Cells
• Humans
• Ligands
• Models, Molecular
• Multiprotein Complexes (chemistry)
• Mutation
• Polymorphism, Genetic
• Recombinant Proteins (chemistry, genetics, metabolism)