Mutations in complement C3 predispose to development of atypical hemolytic uremic syndrome

Abstract

Atypical hemolytic uremic syndrome (aHUS) is a disease of complement dysregulation.In approximately 50% of patients, mutations have been described in the genes encoding the complement regulators factor H, MCP, and factor I or the activator factor B. We report here mutations in the central component of the complement cascade, C3, in association with aHUS. We describe 9 novel C3 mutations in 14 aHUS patients with a persistently low serum C3 level. We have dem- IntroductionMutations in the genes encoding the complement regulators factor H, 1-6 factor I, 7,8 and membrane cofactor protein (MCP; CD46), 9,10 as well as in the activating component factor B, 11 have been detected in approximately 50% of patients with atypical hemolytic uremic syndrome (aHUS). 12 A proportion of the remaining patients have persistently low serum levels of C3. In this study we have examined the hypothesis that mutations in the gene encoding C3 could be associated with aHUS in these patients.C3 is the pivotal component of the complement system. 13 Activation of the classical, lectin, and alternative pathways results in cleavage of C3 to generate C3b and the anaphylatoxin C3a. When C3b is produced, the thioester is cleaved, and then this highly reactive species may bind covalently to targets. Interaction of the zymogen factor B with C3b and subsequent cleavage of factor B by factor D results in formation of the alternative pathway C3 convertase C3bBb. This set of reactions represents an amplification loop.A series of complement regulators including factor H and MCP prevent feedback via this loop by increasing the rate of dissociation of C3bBb and/or by serving as cofactors for the serine protease factor I to cleave C3b. Mutations in the gene encoding factor B were recently found to enhance formation of C3bBb or increase resistance to inactivation. 11 The importance of C3 as a susceptibility factor for human disease has been emphasized by recent studies documenting that a common nonsynonymous coding change in C3 (rs2230199, Arg80Gly, corresponding to C3S and C3F) is both a susceptibility factor for age-related macular degeneration 14 and associated with long-term renal allograft survival. 15 Methods SubjectsIn 2 independent cohorts of aHUS patients (Paris, France and Newcastle upon Tyne, United Kingdom), 26 patients (17 Paris, 9 Newcastle) with a serum C3 level persistently below the lower end of the normal range of 680 to 1380 mg/L were identified. In these patients functionally significant mutations in CFH, MCP, CFI, and CFB had not previously been detected. Mutation screening of C3 was undertaken in these patients.Approval for this study was obtained from the Departement de la Rechereche Clinique et du Developement, DRRC Ile de France, France and the Northern and Mutation screeningThe coding sequence of C3 was amplified with flanking primers (Table S1, available on the Blood website; see the Supplemental Materials link at the top of the online article). Direct sequencing was undertaken using a 96-capillary Sequencer 3700 (Applied Biosyst...

Complement Inhibitor Eculizumab in Atypical Hemolytic Uremic Syndrome

“…Approximately 50% of patients with aHUS have mutations in one of the complement regulatory proteins: Factor H (CFH), factor I (CFI), or membrane co-factor protein (MCP) (3)(4)(5). More recently, mutations in factor B (CFB) and C3 have been associated with aHUS (6,7). The frequencies of homozygous deletions of CFH-related genes CFHR1/CFHR3 and of polymorphisms in CFH, MCP, and C4-binding protein are increased (8 -10).…”

“…All exons of the complement regulatory genes were sequenced as described previously (7,(27)(28)(29). The primer sequences for CFH, CFI, MCP, CFB, C3, and C4BP gene screening are available from the authors on request.…”

A novel hybrid CFH/CFHR3 gene generated by a microhomology-mediated deletion in familial atypical hemolytic uremic syndrome

“…by guest www.bloodjournal.org From previously. [13][14][15][16][17] Genotyping of the following SNPs was undertaken using direct sequencing:…”

Atypical hemolytic uremic syndrome: from diagnosis to treatment

“…Penetrance is also incomplete in aHUS, and seems to be 40%-50% among carriers of CFH, membrane cofactor protein (MCP), and CFI mutations [25]; healthy carriers of C3 and CFB mutations have also been described [26,27]. There are numerous reports describing the onset of aHUS symptoms in association with an environmental trigger.…”