title: A prevalent C3 mutation in aHUS patients causes a direct C3 convertase gain of function.
abstract: Atypical hemolytic uremic syndrome (aHUS) is a rare renal thrombotic microangiopathy commonly associated with rare genetic variants in complement system genes, unique to each patient/family. Here, we report 14 sporadic aHUS patients carrying the same mutation, R139W, in the complement C3 gene. The clinical presentation was with a rapid progression to end-stage renal disease (6 of 14) and an unusually high frequency of cardiac (8 of 14) and/or neurologic (5 of 14) events. Although resting glomerular endothelial cells (GEnCs) remained unaffected by R139W-C3 sera, the incubation of those sera with GEnC preactivated with pro-inflammatory stimuli led to increased C3 deposition, C5a release, and procoagulant tissue-factor expression. This functional consequence of R139W-C3 resulted from the formation of a hyperactive C3 convertase. Mutant C3 showed an increased affinity for factor B and a reduced binding to membrane cofactor protein (MCP; CD46), but a normal regulation by factor H (FH). In addition, the frequency of at-risk FH and MCP haplotypes was significantly higher in the R139W-aHUS patients, compared with normal donors or to healthy carriers. These genetic background differences could explain the R139W-aHUS incomplete penetrance. These results demonstrate that this C3 mutation, especially when associated with an at-risk FH and/or MCP haplotypes, becomes pathogenic following an inflammatory endothelium-damaging event.
authors.affiliation: Cordeliers Research Center, INSERM Unité Mixte de Recherche en Santé, Paris, France.
authors.forename: Lubka T
authors.initials: LT
authors.lastname: Roumenina
authors.forename: Marie
authors.initials: M
authors.lastname: Frimat
authors.forename: Elizabeth C
authors.initials: EC
authors.lastname: Miller
authors.forename: Francois
authors.initials: F
authors.lastname: Provot
authors.forename: Marie-Agnes
authors.initials: MA
authors.lastname: Dragon-Durey
authors.forename: Pauline
authors.initials: P
authors.lastname: Bordereau
authors.forename: Sylvain
authors.initials: S
authors.lastname: Bigot
authors.forename: Christophe
authors.initials: C
authors.lastname: Hue
authors.forename: Simon C
authors.initials: SC
authors.lastname: Satchell
authors.forename: Peter W
authors.initials: PW
authors.lastname: Mathieson
authors.forename: Christiane
authors.initials: C
authors.lastname: Mousson
authors.forename: Christian
authors.initials: C
authors.lastname: Noel
authors.forename: Catherine
authors.initials: C
authors.lastname: Sautes-Fridman
authors.forename: Lise
authors.initials: L
authors.lastname: Halbwachs-Mecarelli
authors.forename: John P
authors.initials: JP
authors.lastname: Atkinson
authors.forename: Arnaud
authors.initials: A
authors.lastname: Lionet
authors.forename: Veronique
authors.initials: V
authors.lastname: Fremeaux-Bacchi
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D019943:Amino Acid Substitution; D065766:Atypical Hemolytic Uremic Syndrome; D002478:Cells, Cultured / Q000187:drug effects; D002675:Child, Preschool; D003176:Complement C3 / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D011415:Complement Factor B / Q000378:metabolism; D018450:Disease Progression; D042783:Endothelial Cells / Q000187:drug effects; D004730:Endothelium, Vascular / Q000378:metabolism / Q000473:pathology; D005260:Female; D006239:Haplotypes / Q000235:genetics; D006463:Hemolytic-Uremic Syndrome / Q000097:blood / Q000150:complications / Q000235:genetics* / Q000276:immunology; D006801:Humans; D007223:Infant; D007676:Kidney Failure, Chronic / Q000209:etiology; D007678:Kidney Glomerulus / Q000473:pathology; D008297:Male; D051916:Membrane Cofactor Protein / Q000378:metabolism; D008875:Middle Aged; D008958:Models, Molecular; D020125:Mutation, Missense; D019683:Penetrance; D017354:Point Mutation; D011487:Protein Conformation; D020349:Surface Plasmon Resonance; D055815:Young Adult
chemical_list: C497857:CD46 protein, human; D003176:Complement C3; D051916:Membrane Cofactor Protein; D011415:Complement Factor B