Functional Evaluation of Factor H genetic and Acquired Abnormalities: Application for Atypical Hemolytic Uremic Syndrome (aHUS)

Roumenina, Lubka T.; Roquigny, Roxane; Blanc, Caroline; Poulain, Nelly; Ngo, Stéphanie; Dragon-Durey, Marie-Agnès; Frémeaux‐Bacchi, Véronique

doi:10.1007/978-1-62703-724-2_19

Cited by 16 publications

(25 citation statements)

References 28 publications

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“…choring C-terminal domains and markedly perturbed cell surface protection (20,23,27,39). In individuals with aHUS-associated FH mutations, a disturbance in cell protection against complement attack is observed similar to what is observed in individuals with anti-FH Abs (27,28,38,39,42,43). In contrast, in GP patients, FH mutations are predominantly located in the N-terminal region of FH, and they mainly affect fluid-phase control (15,16,44).…”

Section: Discussionmentioning

confidence: 68%

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Anti–Factor H Autoantibodies in C3 Glomerulopathies and in Atypical Hemolytic Uremic Syndrome: One Target, Two Diseases

Blanc

Togarsimalemath

Chauvet

et al. 2015

The Journal of Immunology

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Autoantibodies targeting factor H (FH), which is a main alternative complement pathway regulatory protein, have been well characterized in atypical hemolytic uremic syndrome (aHUS) but have been less well described in association with alternative pathway–mediated glomerulopathies (GP). In this study, we studied 17 patients presenting with GP who were positive for anti-FH IgG. Clinical data were collected and biological characteristics were compared with those of patients presenting with anti-FH Ab-associated aHUS. In contrast to the aHUS patients, the GP patients had no circulating FH-containing immune complexes, and their anti-FH IgG had a weaker affinity for FH. Functional studies demonstrated that these Abs induced no perturbations in FH cell surface protection or the binding of FH to its ligand. However, anti-FH IgG samples isolated from three patients were able to affect the factor I cofactor activity of FH. Epitope mapping identified the N-terminal domain of FH as the major binding site for GP patient IgG. No homozygous deletions of the CFHR1 and CFHR3 genes, which are frequently associated with the anti-FH Ab in aHUS patients, were found in the GP patients. Finally, anti-FH Abs were frequently associated with the presence of C3 nephritic factor in child GP patients and with monoclonal gammopathy in adult GP patients, who frequently showed Ig Lchain restriction during reactivity against factor H. These data provide deeper insights into the pathophysiological differences between aHUS and GP, demonstrating heterogeneity of anti-FH IgG.

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Section: Discussionmentioning

confidence: 68%

“…This assay was performed as previously described (38,39). Samples from 12 aHUS patients with anti-FH Abs collected during the acute phase and from 17 GP patients were tested.…”

Section: Cell Lysis Assaysmentioning

confidence: 99%

Anti–Factor H Autoantibodies in C3 Glomerulopathies and in Atypical Hemolytic Uremic Syndrome: One Target, Two Diseases

Blanc

Togarsimalemath

Chauvet

et al. 2015

The Journal of Immunology

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100

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“…These defects translate to overactivity of the terminal complement pathway. As a result, the presence of FH mutations in patients' sera induces a spontaneous lysis of sheep erythrocytes, 34,35 and the presence of FB or C3 mutations causes In the GV/GD column, 0 indicates no predicted defect, and a number$15 predicts functional defect. In the semantics of Mutation Taster, polymorphism means mutation without predicted functional significance.…”

Section: Discussionmentioning

confidence: 99%

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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“…Similarly, normal levels of abovementioned complement factors do not rule out the diagnosis of aHUS, because a majority of mutations cause functional impairment instead of quantitative defects. The hemolytic assay can be used to assess the CFH function [48][49][50]. In this assay, patient specimens are incubated with sheep red blood cells (RBCs) that have been known as "non-activating cells" leading no amplification of C3b on its cell surface.…”

Section: Complement Assessment In Ahusmentioning

confidence: 99%

Atypical hemolytic uremic syndrome

2017

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Atypical hemolytic uremic syndrome (aHUS) is a thrombotic microangiopathy (TMA) characterized by microangiopathic hemolytic anemia, thrombocytopenia, and acute renal failure. Most cases of aHUS are caused by uncontrolled complement activation due to genetic mutations in the alternative pathway of complement. More recently, mutations in the gene of coagulation system have also been identified in patients with aHUS. In Japan, the recent studies of aHUS have identified the unique genetic characteristics in our country and enabled us to revise the diagnostic criteria. In this article, we review the classification of TMAs and describe the pathophysiology, diagnosis, and management of aHUS. We also highlight current progress in clinical and basic research of the patients with aHUS in Japan.

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Functional Evaluation of Factor H genetic and Acquired Abnormalities: Application for Atypical Hemolytic Uremic Syndrome (aHUS)

Cited by 16 publications

References 28 publications

Anti–Factor H Autoantibodies in C3 Glomerulopathies and in Atypical Hemolytic Uremic Syndrome: One Target, Two Diseases

Anti–Factor H Autoantibodies in C3 Glomerulopathies and in Atypical Hemolytic Uremic Syndrome: One Target, Two Diseases

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

Atypical hemolytic uremic syndrome

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