Mutations of Factor H Impair Regulation of Surface-bound C3b by Three Mechanisms in Atypical Hemolytic Uremic Syndrome

Lehtinen, Markus J.; Rops, Angelique L.; Isenman, David E.; Vlag, Johan van der; Jokiranta, T. Sakari

doi:10.1074/jbc.m900814200

Cited by 89 publications

(121 citation statements)

References 47 publications

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“…Similar results were obtained for 17 mutations in the C-terminal 19 and 20 domains of FH, for which the functional defect was well characterized [31][32][33] (data summarized in ref.…”

Section: Prediction For the Damaging Probability Of Fb Mutationssupporting

confidence: 73%

“…Similar results were obtained for the mutations in the C terminus of FH, well known for their functional defect and association with aHUS. 2,[31][32][33] In conclusion, although some FB mutations induce complement overactivation and predispose to aHUS, others have a normal functional activity and hence, are benign and unlikely to be related to the disease. In-depth screening of all susceptibility genes as well as for the presence of anti-FH antibodies is necessary in all patients with identified FB mutations to identify other abnormalities affecting the disease occurrence, especially in the presence of low C3 levels.…”

Section: Discussionmentioning

confidence: 99%

“…In the 1000 Genomes database, 26 32 polymorphisms of FB have been reported (Supplemental Figure 1). Among them, three have been identified in aHUS patients (I217L Figure 1).…”

Section: Fb Genetic Changes In the Normal Populationmentioning

confidence: 99%

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

Marinozzi

Vergoz

Rybkine

et al. 2014

Journal of the American Society of Nephrology

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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.

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“…Similar results were obtained for 17 mutations in the C-terminal 19 and 20 domains of FH, for which the functional defect was well characterized [31][32][33] (data summarized in ref.…”

Section: Prediction For the Damaging Probability Of Fb Mutationssupporting

confidence: 73%

Section: Discussionmentioning

confidence: 99%

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

Marinozzi

Vergoz

Rybkine

et al. 2014

Journal of the American Society of Nephrology

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“…This interaction prevents inadvertent action of the AP of complement on host cells and mediates its ability to distinguish between host cells and pathogens that do not have such glycans (57). The relevance of FH-glycan interaction in protecting cells and tissues from complement-activating products is highlighted by data that gene mutations resulting in reduced capability of FH to bind cell surfaces result in uncontrolled complement activation and aHUS (58,59). Our present results of C3bB and C3bBb assembly in the presence of HS or SA show that even in this more physiological pattern, FH does not substantially affect C3 proconvertase assembly but has a strong inhibitory effect on C3 convertase formation.…”

Section: Discussionmentioning

confidence: 99%

Insights into the Effects of Complement Factor H on the Assembly and Decay of the Alternative Pathway C3 Proconvertase and C3 Convertase

Bettoni

Bresin

Noris

et al. 2016

Journal of Biological Chemistry

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The activated fragment of C3 (C3b) and factor B form the C3 proconvertase (C3bB), which is cleaved by factor D to C3 convertase ( Immunol. 122, 75-81) indicated that the complement alternative pathway regulator factor H (FH) competes with factor B for C3b binding; however, the capability of FH to prevent C3bB assembly has not been formally investigated. Moreover, in the few published studies FH did not favor C3bB dissociation. Whether FH may affect C3bBb formation from C3bB is unknown. We set up user-friendly assays based on combined microplate/Western blotting techniques that specifically detect either C3bB or C3bBb, with the aim of investigating the effect of FH on C3bB assembly and decay and C3bBb formation and decay. We document that FH does not affect C3bB assembly, indicating that FH does not efficiently compete with factor B for C3b binding. We also found that FH does not dissociate C3bB. FH showed a strong C3bBb decay-accelerating activity, as reported previously, and also exerted an apparent inhibitory effect on C3bBb formation. The latter effect was not fully attributable to a rapid FH-mediated dissociation of C3bBb complexes, because blocking decay with properdin and C3 nephritic factor did not restore C3bBb formation. FH almost completely prevented release of the smaller cleavage subunit of FB (Ba), without modifying the amount of C3bB complexes, suggesting that FH inhibits the conversion of C3bB to C3bBb. Thus, the inhibitory effect of FH on C3bBb formation is likely the sum of inhibition of C3bB conversion to C3bBb and of C3bBb decay acceleration. Further studies are required to confirm these findings in physiological cell-based settings.The complement system is a complex network of plasma proteins that cooperate in the defense against foreign microorganisms and in the maintenance of tissue homeostasis (1-3). Interest in the complement system was rekindled in the past decade by accumulating evidence that genetically determined complement dysregulation is involved in two rare devastating disorders of the kidney, atypical hemolytic uremic syndrome (aHUS) 3 and C3 glomerulopathy (C3G) (4 -8), as well as in age-related macular degeneration, the leading cause of blindness for older people (9). Finding that treatment with eculizumab (10), a monoclonal antibody that blocks the formation of terminal complement complex C5b-9, efficiently cured aHUS (11, 12) and C3G (13-15) further corroborated the role of complement in human disease (16).Complement can be triggered by three activation pathways, the classical, the lectin, and the alternative (AP) pathways, all leading to the formation of unstable protease complexes, named C3 convertases, that cleave the inactive central component C3 into C3a and C3b fragments. C3b molecules deposited on pathogens or damaged self-cells provide a molecular platform for the formation of an active AP C3 convertase, C3bBb, which enzymatically generates many more C3b molecules, resulting in a positive feedback loop. Notably, the AP C3 convertase is crucial within the complement ca...

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“…More than 50% of CFH mutations are in SCR20 [38]. Functional studies to analyse the interaction between CFH and its ligands (C3b, glycosaminoglycans, heparin and endothelial cells) frequently demonstrate alteration of the binding of CFH19-20 mutants [50,[59][60][61]. Some mutations (named type 1 mutations) are associated with a quantitative deficiency in CFH (decreased CFH plasma levels), but many, including the majority of mutations in SCR19 and 20, are associated with normal plasma levels of CFH, the mutant CFH being functionally deficient (type 2 mutations).…”

Section: Complement Dysregulation In Ahus Cfh Mutationsmentioning

confidence: 99%

Atypical Hemolytic Uremic Syndrome

Loirat¹,

Frémeaux‐Bacchi²

2016

Pediatric Kidney Disease

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Hemolytic uremic syndrome (HUS) is defined by the triad of mechanical hemolytic anemia, thrombocytopenia and renal impairment. Atypical HUS (aHUS) defines non Shiga-toxin-HUS and even if some authors include secondary aHUS due to Streptococcus pneumoniae or other causes, aHUS designates a primary disease due to a disorder in complement alternative pathway regulation. Atypical HUS represents 5 -10% of HUS in children, but the majority of HUS in adults. The incidence of complement-aHUS is not known precisely. However, more than 1000 aHUS patients investigated for complement abnormalities have been reported. Onset is from the neonatal period to the adult age. Most patients present with hemolytic anemia, thrombocytopenia and renal failure and 20% have extra renal manifestations. Two to 10% die and one third progress to end-stage renal failure at first episode. Half of patients have relapses. Mutations in the genes encoding complement regulatory proteins factor H, membrane cofactor protein (MCP), factor I or thrombomodulin have been demonstrated in 20-30%, 5-15%, 4-10% and 3-5% of patients respectively, and mutations in the genes of C3 convertase proteins, C3 and factor B, in 2-10% and 1-4%. In addition, 6-10% of patients have anti-factor H antibodies. Diagnosis of aHUS relies on 1) No associated disease 2) No criteria for Shigatoxin-HUS (stool culture and PCR for Shiga-toxins; serology for anti-lipopolysaccharides antibodies) 3) No criteria for thrombotic thrombocytopenic purpura (serum ADAMTS 13 activity > 10%). Investigation of the complement system is required (C3, C4, factor H and factor I plasma concentration, MCP expression on leukocytes and anti-factor H antibodies; genetic screening to identify risk factors). The disease is familial in approximately 20% of pedigrees, with an autosomal recessive or dominant mode of transmission. As penetrance of the disease is 50%, genetic counseling is difficult. Plasmatherapy has been first line treatment until presently, without unquestionable demonstration of efficiency. There is a high risk of post-transplant recurrence, except in MCP-HUS. Case reports and two phase II trials show an impressive efficacy of the complement C5 blocker eculizumab, suggesting it will be the next standard of care. Except for patients treated by intensive plasmatherapy or eculizumab, the worst prognosis is in factor H-HUS, as mortality can reach 20% and 50% of survivors do not recover renal function. Half of factor I-HUS progress to end-stage renal failure. Conversely, most patients with MCP-HUS have preserved renal function. Anti-factor H antibodies-HUS has favourable outcome if treated early.

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Mutations of Factor H Impair Regulation of Surface-bound C3b by Three Mechanisms in Atypical Hemolytic Uremic Syndrome

Cited by 89 publications

References 47 publications

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

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

Insights into the Effects of Complement Factor H on the Assembly and Decay of the Alternative Pathway C3 Proconvertase and C3 Convertase

Atypical Hemolytic Uremic Syndrome

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