A Large Family with a Gain-of-Function Mutation of Complement C3 Predisposing to Atypical Hemolytic Uremic Syndrome, Microhematuria, Hypertension and Chronic Renal Failure

Lhotta, Karl; Janecke, Andreas R.; Scheiring, Johanna; Petzlberger, Barbara; Giner, Thomas; Fally, Verena; Würzner, Reinhard; Zimmerhackl, Lothar Bernd; Mayer, Gert; Frémeaux‐Bacchi, Véronique

doi:10.2215/cjn.06281208

Cited by 44 publications

(46 citation statements)

References 29 publications

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“…In published series, C3 mutation screening was limited to patients with low C3 levels (8,26); our data suggest that it should be performed in all patients.…”

Section: Discussionmentioning

confidence: 88%

Relative Role of Genetic Complement Abnormalities in Sporadic and Familial aHUS and Their Impact on Clinical Phenotype

Noris¹,

Caprioli²,

Bresin³

et al. 2010

Clinical Journal of the American Society of Nephrology

931

1,194

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Background and objectives: Hemolytic uremic syndrome (HUS) is characterized by microangiopathic hemolytic anemia, thrombocytopenia, and renal impairment. Most childhood cases are caused by Shiga toxin-producing bacteria. The other form, atypical HUS (aHUS), accounts for 10% of cases and has a poor prognosis. Genetic complement abnormalities have been found in aHUS.Design, setting, participants, and measurements: We screened 273 consecutive patients with aHUS for complement abnormalities and studied their role in predicting clinical phenotype and response to treatment. We compared mutation frequencies and localization and clinical outcome in familial (82) and sporadic (191) cases.Results: In >70% of sporadic and familial cases, gene mutations, disease-associated factor H (CFH) polymorphisms, or anti-CFH autoantibodies were found. Either mutations or CFH polymorphisms were also found in the majority of patients with secondary aHUS, suggesting a genetic predisposition. Familial cases showed a higher prevalence of mutations in SCR20 of CFH and more severe disease than sporadic cases. Patients with CFH or THBD (thrombomodulin) mutations had the earliest onset and highest mortality. Membrane-cofactor protein (MCP) mutations were associated with the best prognosis. Plasma therapy induced remission in 55 to 80% of episodes in patients with CFH, C3, or THBD mutations or autoantibodies, whereas patients with CFI (factor I) mutations were poor responders. aHUS recurred frequently after kidney transplantation except for patients with MCP mutations.Conclusions: Results underline the need of genetic screening for all susceptibility factors as part of clinical management of aHUS and for identification of patients who could safely benefit from kidney transplant.

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“…In published series, C3 mutation screening was limited to patients with low C3 levels (8,26); our data suggest that it should be performed in all patients.…”

Section: Discussionmentioning

confidence: 88%

Relative Role of Genetic Complement Abnormalities in Sporadic and Familial aHUS and Their Impact on Clinical Phenotype

Noris¹,

Caprioli²,

Bresin³

et al. 2010

Clinical Journal of the American Society of Nephrology

931

1,194

View full text Add to dashboard Cite

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“…Sporadic aHUS was found in 97 patients, and 33 patients were identified in 14 different pedigrees. 15,16,[21][22][23][24][25][26][27][28][29][30][31][32][33] Table 1). Fifteen of the 42 mutations were recurrent (identified in $2 unrelated aHUS patients from the same or different cohorts; Figure 1; supplemental Table 2).…”

Section: Resultsmentioning

confidence: 99%

Mapping interactions between complement C3 and regulators using mutations in atypical hemolytic uremic syndrome

Schramm

Roumenina

Rybkine

et al. 2015

Blood

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116

130

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Key Points• C3 mutations in aHUS commonly result in impaired complement regulation, C3 consumption, and a poor renal outcome.• C3 mutations tend to cluster at the protein surface and facilitate mapping of putative binding sites for the regulatory proteins.The pathogenesis of atypical hemolytic uremic syndrome (aHUS) is strongly linked to dysregulation of the alternative pathway of the complement system. Mutations in complement genes have been identified in about two-thirds of cases, with 5% to 15% being in C3. In this study, 23 aHUS-associated genetic changes in C3 were characterized relative to their interaction with the control proteins factor H (FH), membrane cofactor protein (MCP; CD46), and complement receptor 1 (CR1; CD35). In surface plasmon resonance experiments, 17 mutant recombinant proteins demonstrated a defect in binding to FH and/or MCP, whereas 2 demonstrated reduced binding to CR1. In the majority of cases, decreased binding affinity translated to a decrease in proteolytic inactivation (known as cofactor activity) of C3b via FH and MCP. These results were used to map the putative binding regions of C3b involved in the interaction with MCP and CR1 and interrogated relative to known FH binding sites. Seventy-six percent of patients with C3 mutations had low C3 levels that correlated with disease severity. This study expands our knowledge of the functional consequences of aHUS-associated C3 mutations relative to the interaction of C3 with complement regulatory proteins mediating cofactor activity. (Blood. 2015;125(15):2359-2369

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“…This has been observed for all mutations, i.e. CFH, MCP, CFI [18,38,46,85], CFB [80], C3 [18,83,84] and THBD [18,45]. The identified mutation therefore appears as a risk factor to the disease rather than its direct and unique cause.…”

Section: Familial Ahus Incomplete Penetrance and Genetic Variabilitymentioning

confidence: 85%

“…Fivety seven per cent of C3-mutated patients and 88% of THBD-mutated patients who received plasmatherapy in the Italian Registry had a response (either complete or partial remission (hematological remission with renal sequel), and 43% and 13% respectively progressed to death or ESRF [18]. Remission with PE or PI has been reported in 2 patients with C3 mutation [84,121] and 3 with CFB mutation [80][81][82].…”

Section: Plasmatherapy In Patients With C3 Cfb or Thbd Mutationmentioning

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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A Large Family with a Gain-of-Function Mutation of Complement C3 Predisposing to Atypical Hemolytic Uremic Syndrome, Microhematuria, Hypertension and Chronic Renal Failure

Cited by 44 publications

References 29 publications

Relative Role of Genetic Complement Abnormalities in Sporadic and Familial aHUS and Their Impact on Clinical Phenotype

Relative Role of Genetic Complement Abnormalities in Sporadic and Familial aHUS and Their Impact on Clinical Phenotype

Mapping interactions between complement C3 and regulators using mutations in atypical hemolytic uremic syndrome

Atypical Hemolytic Uremic Syndrome

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