Characterization of a Factor H Mutation That Perturbs the Alternative Pathway of Complement in a Family with Membranoproliferative GN

Wong, Edwin K.S.; Anderson, Holly E.; Herbert, Andrew P.; Challis, Rachel; Brown, Paul A.; Reis, Geisilaine Soares dos; Tellez, James O.; Strain, Lisa; Fluck, Nicholas; Humphrey, Ann; MacLeod, Alison; Richards, Anna; Ahlert, Daniel; Santibanez‐Koref, Mauro; Barlow, Paul N.; Marchbank, Kevin J.; Harris, Claire L.; Goodship, Timothy H.J.; Kavanagh, David

doi:10.1681/asn.2013070732

Cited by 39 publications

(46 citation statements)

References 35 publications

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“…Mutation screening of CFH , CFI , CFB , CD46 , and C3 was undertaken using Sanger sequencing as previously described. Genotyping of the following SNPs CFH −331C>T (rs3753394), CFH c.184G>A; p.Val62Ile (rs800292), CFH c.1204T>C; p.Tyr402His (rs1061170), CFH c.2016A>G; p.Gln672Gln (rs3753396), CFH IVS15 −543G>A intron 15 (rs1410996), CFH c.2808G>T; p.Glu936Asp (rs1065489), CD46 −652A>G (rs2796267), CD46 −366A>G (rs2796268), CD46 IVS9 −78G>A (rs1962149), CD46 IVS12 +638G>A (rs859705), and CD46 c.4070T>C (rs7144) was used to determine CFH and CD46 haplotypes .…”

Section: Methodsmentioning

confidence: 99%

The role of ADAMTS‐13 activity and complement mutational analysis in differentiating acute thrombotic microangiopathies

Phillips

Westwood

Brocklebank

et al. 2016

Journal of Thrombosis and Haemostasis

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Essentials Molecular diagnostics has improved the differentiation of acute thrombotic microangiopathys (TMAs). Atypical hemolytic uremic syndrome may have features mimicking thrombotic thrombocytopenic purpura. We identified novel complement mutations and a high incidence of CD46, with favorable long term outcomes. Complement mutation analysis in TMA where the diagnosis is unclear and ADAMTS‐13 activity is >10%. SummaryBackgroundDifferentiation of acute thrombotic microangiopathy (TMA) at presentation has historically been dependent on clinical parameters. Confirmation of thrombotic thrombocytopenic purpura (TTP) is increasingly reliant on demonstrating deficient ADAMTS‐13 activity. The identification of alternative complement pathway abnormalities in atypical hemolytic uremic syndrome (aHUS), along with the proven efficacy of terminal complement inhibitors in treatment, has increased the need for rapid differentiation of TTP from aHUS.ObjectivesWe describe the clinical phenotype and nature of complement mutations in a cohort of aHUS patients referred as acute TMAs.Patients/methodsFourteen consecutive aHUS patients were screened for mutations in C3,CD46,CFH,CFI, and CFB, as well as factor H (FH) antibodies. All aHUS patients had ADAMTS‐13 activity > 10%.ResultsOf 14 aHUS patients, 11 (79%) had platelet counts < 30 × 109/L during the acute phase. Median presenting creatinine level was 295 μmol L−1, while five (36%) of 14 presented with a serum creatinine level < 200 μmol L−1. Alternative complement pathway mutations were detected in 9 (64%) of 14 patients, including CD46 mutations in five (36%) of 14 patients. Patients were identified with novel mutations in CFB and C3 that have not been previously reported.ConclusionsWe demonstrate that diagnostic differentiation based on platelet count and renal function is insufficient to predict an underlying complement mutation in some aHUS cases. Specifically, we demonstrate a high frequency of functionally significant CD46 mutations which may mimic TTP. ADAMTS‐13 activity > 10% in a patient with a TMA should necessitate genetic screening for complement abnormalities.

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Section: Methodsmentioning

confidence: 99%

The role of ADAMTS‐13 activity and complement mutational analysis in differentiating acute thrombotic microangiopathies

Phillips

Westwood

Brocklebank

et al. 2016

Journal of Thrombosis and Haemostasis

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“…Decay acceleration on sheep erythrocytes was performed as previously described 32 and in Supplemental Material. Briefly, FH/FHR3 hybrid from the patient and FH from controls were purified by immunoaffinity chromatography as above and gel filtered into PBS.…”

Section: Cell Surface Decay Acceleration Assaysmentioning

confidence: 99%

A De Novo Deletion in the Regulators of Complement Activation Cluster Producing a Hybrid Complement Factor H/Complement Factor H–Related 3 Gene in Atypical Hemolytic Uremic Syndrome

Challis¹,

Araujo²,

Wong³

et al. 2015

JASN

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The regulators of complement activation cluster at chromosome 1q32 contains the complement factor H (CFH) and five complement factor H-related (CFHR) genes. This area of the genome arose from several large genomic duplications, and these low-copy repeats can cause genome instability in this region. Genomic disorders affecting these genes have been described in atypical hemolytic uremic syndrome, arising commonly through nonallelic homologous recombination. We describe a novel CFH/CFHR3 hybrid gene secondary to a de novo 6.3-kb deletion that arose through microhomology-mediated end joining rather than nonallelic homologous recombination. We confirmed a transcript from this hybrid gene and showed a secreted protein product that lacks the recognition domain of factor H and exhibits impaired cell surface complement regulation. The fact that the formation of this hybrid gene arose as a de novo event suggests that this cluster is a dynamic area of the genome in which additional genomic disorders may arise.

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“…In ∼30% of cases, it is associated with FH mutations located mainly in the C-terminal domain (14), whereas mutations in the N-terminal domain are associated with both aHUS and GP (13,(15)(16)(17).…”

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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

104

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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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Characterization of a Factor H Mutation That Perturbs the Alternative Pathway of Complement in a Family with Membranoproliferative GN

Cited by 39 publications

References 35 publications

The role of ADAMTS‐13 activity and complement mutational analysis in differentiating acute thrombotic microangiopathies

The role of ADAMTS‐13 activity and complement mutational analysis in differentiating acute thrombotic microangiopathies

A De Novo Deletion in the Regulators of Complement Activation Cluster Producing a Hybrid Complement Factor H/Complement Factor H–Related 3 Gene in Atypical Hemolytic Uremic Syndrome

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

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