Complement Factor B Mutations in Atypical Hemolytic Uremic Syndrome—Disease-Relevant or Benign?

• Published in: Journal of the American Society of Nephrology Vol. 25; no. 9; pp. 2053 - 2065
• Main Authors: MARINOZZI, Maria Chiara, VERGOZ, Laura, SMITH, Richard J, NORIS, Marina, HALBWACHS-MECARELLI, Lise, DONADELLI, Roberta, FREMEAUX-BACCHI, Veronique, ROUMENINA, Lubka T, RYBKINE, Tania, NGO, Stephanie, BETTONI, Serena, PASHOV, Anastas, CAYLA, Mathieu, TABARIN, Fanny, JABLONSKI, Mathieu, HUE, Christophe
• Format: Journal Article
• Language: English
• Published: Washington, DC American Society of Nephrology 01.09.2014
• Subjects: Amino Acid Substitution; Atypical Hemolytic Uremic Syndrome - genetics; Atypical Hemolytic Uremic Syndrome - immunology; Basic Research; Binding Sites - genetics; Biological and medical sciences; Complement C3 Convertase, Alternative Pathway - chemistry; Complement C3 Convertase, Alternative Pathway - genetics; Complement C3 Convertase, Alternative Pathway - metabolism; Complement C3b - metabolism; Complement C5 Convertase, Alternative Pathway - chemistry; Complement C5 Convertase, Alternative Pathway - genetics; Complement C5 Convertase, Alternative Pathway - metabolism; Complement Factor B - chemistry; Complement Factor B - genetics; Complement Factor B - metabolism; Complement Pathway, Alternative - genetics; Computer Simulation; Gene Frequency; Hematologic and hematopoietic diseases; Human Umbilical Vein Endothelial Cells; Humans; Ligands; Medical sciences; Models, Molecular; Multiprotein Complexes - chemistry; Mutation; Nephrology. Urinary tract diseases; Nephropathies. Renovascular diseases. Renal failure; Platelet diseases and coagulopathies; Polymorphism, Genetic; Recombinant Proteins - chemistry; Recombinant Proteins - genetics; Recombinant Proteins - metabolism; Renal failure; Kidney disease; Thrombocytopenia; Nephrology; Urinary system disease; Hemolytic uremic syndrome; Disease; Acute; Complement factor B; Cardiovascular disease; Hemopathy; Thrombohemolytic microangiopathy; Urology; Vascular disease; Platelet; Hemolytic anemia; Renal failure; Genetics; Atypical; Mutation
• ISSN: 1046-6673; 1533-3450
• DOI: 10.1681/asn.2013070796

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.