A Novel Non-Synonymous Polymorphism (p.Arg240His) in C4b-Binding Protein Is Associated with Atypical Hemolytic Uremic Syndrome and Leads to Impaired Alternative Pathway Cofactor Activity

Blom, Anna M.; Bergström, Frida; Edey, Matthew; Diaz-Torres, Martha; Kavanagh, David; Lampe, Anne Katrin; Goodship, Judith A.; Strain, Lisa; Moghal, Nadeem; McHugh, Mary L.; Inward, Carol; Tomson, Charles; Frémeaux‐Bacchi, Véronique; Villoutreix, Bruno O.; Goodship, Timothy H.J.

doi:10.4049/jimmunol.180.9.6385

Cited by 52 publications

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References 42 publications

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“…In addition, age at onset and severity of the disease may vary among family members with the same mutation ( Figure 5). The role of various polymorphisms as independent or additional susceptibility factors to aHUS has been demonstrated in the genes encoding CFH [18,26,[85][86][87], MCP [26,86], CFHR1 [88] or C4b-BP [89]. These sequence variations in the human genome are mostly changes of a single base (Single Nucleotide Polymorphism, SNP), which can be associated with a change of amino-acid in the protein, inducing a partial gain or loss of function.…”

Section: Familial Ahus Incomplete Penetrance and Genetic Variabilitymentioning

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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Section: Familial Ahus Incomplete Penetrance and Genetic Variabilitymentioning

confidence: 99%

Atypical Hemolytic Uremic Syndrome

Loirat¹,

Frémeaux‐Bacchi²

2016

Pediatric Kidney Disease

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“…In the first, C3b was deposited on the sheep erythrocytes by sequential incubation of C1, C4, C2 and C3 [15]. To cleave the C3b, the erythrocytes were incubated with 5 mg/mL FI and 100 mg/mL C4BP at 371C for 60 min.…”

Section: Fi Degradation Of Surface-bound C3bmentioning

confidence: 99%

“…The familial form of aHUS has now been shown to be associated with genetic abnormalities in complement regulators like factor H (FH) [3][4][5][6], factor I (FI) [4,[7][8][9][10], membrane cofactor protein (MCP) Ã These authors contributed equally to this work. 172 [4,[11][12][13][14], C4b-binding protein (C4BP) [15], factor B (FB) [16] and C3 [17] or autoantibodies against FH [18,19]. The mutations and polymorphisms in these proteins are mostly found in heterozygous form and can affect both the secretion and function of the proteins, leading to impaired regulation of the alternative pathway of the complement system [2].…”

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Mutations in complement factor I as found in atypical hemolytic uremic syndrome lead to either altered secretion or altered function of factor I

et al. 2009

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The complement system is regulated by inhibitors such as factor I (FI), a serine protease that degrades activated complement factors C4b and C3b in the presence of specific cofactors. Mutations and polymorphisms in FI and its cofactors are associated with atypical hemolytic uremic syndrome (aHUS). All 14 complement factor I mutations associated with aHUS analyzed in this study were heterozygous and generated premature stop codons (six) or amino acid substitutions (eight). Almost all of the mutants were expressed by human embryonic kidney 293 cells but only six mutants were secreted into the medium, three of which were at lower levels than WT. The remaining eight mutants were not secreted but sensitive to deglycosylation with endoglycosidase H, indicating that they were retained early in the secretory pathway. Six secreted mutants were purified and five of them were functionally altered in degradation of C4b/C3b in the fluid-phase in the presence of various cofactors and on endothelial cells. Three mutants cleaved surfacebound C3b less efficiently than WT. The D501N mutant was severely impaired both in solution and on surface irrespective of the cofactor used. In conclusion, mutations in complement factor I affect both secretion and function of FI, which leads to impaired regulation of the complement system in aHUS.Key words: Atypical hemolytic uremic syndrome . Complement . Factor I IntroductionHemolytic uremic syndrome (HUS) is characterized by microangiopathic hemolytic anemia, thrombocytopenia and acute renal failure [1]. The typical form (diarrhea-positive HUS), which affects 90% of the HUS patients, is associated with infection of Shiga toxin-secreting Escherichia coli. Patients, who are mainly children, suffer from bloody diarrhea, recurrences are uncommon and their prognoses are often good [1]. The other form, called atypical hemolytic uremic syndrome (aHUS), occurs at any age, may be sporadic or familial and has a poor prognosis as approximately 50% of the patients progress to end-stage renal disease and 25% die during the acute phase of the disease. The sporadic form of aHUS may be triggered by non-enteric infections, viruses, pregnancy, drugs, malignancies or transplantation [2]. The familial form of aHUS has now been shown to be associated with genetic abnormalities in complement regulators like factor H (FH) [3][4][5][6], factor I (FI) [4,[7][8][9][10], membrane cofactor protein (MCP) Ã These authors contributed equally to this work. 172 [4,[11][12][13][14], C4b-binding protein (C4BP) [15], factor B (FB) [16] and C3 [17] or autoantibodies against FH [18,19]. The mutations and polymorphisms in these proteins are mostly found in heterozygous form and can affect both the secretion and function of the proteins, leading to impaired regulation of the alternative pathway of the complement system [2]. Since many of the patients carry several heterozygous mutations or polymorphisms in different genes, it has been suggested that a combination of several simultaneous hits strongly predisposes to aHUS [20].The c...

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“…At present, only one functional non-synonymous polymorphism (R240H) has been identified that does not affect expression, but C3b binding and its cofactor functions both in fluid phase and on the cell surface are diminished. 17 This polymorphism has been associated with aHUS, a disease in which excessive complement activation was shown to play a pathogenic role. The anti-C5 mAb eculizumab is currently the only accepted treatment.…”

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confidence: 99%