The development of atypical haemolytic-uraemic syndrome is influenced by susceptibility factors in factor H and membrane cofactor protein: evidence from two independent cohorts

Frémeaux‐Bacchi, Véronique; Kemp, Elizabeth J.; Goodship, Judith A.; Dragon-Durey, Marie-Agnès; Strain, Lisa; Loirat, Chantal; Deng, Hong−Wen; Goodship, Timothy H.J.

doi:10.1136/jmg.2005.030783

Cited by 161 publications

(120 citation statements)

References 24 publications

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“…The haplotype CD46 GGAAC , which is associated with an increased risk of aHUS, 38 is defined by the following single nucleotide polymorphisms: Ϫ652 AϾG (rs2796267), Ϫ366 AϾG (rs2796268), IVS9-78 GϾA (rs1962149), IVS12 ϩ 638 GϾA (rs859705), and c.4070 TϾC (rs7144). The at-risk haplotype was not available for three patients.…”

Section: Methodsmentioning

confidence: 99%

Pregnancy-Associated Hemolytic Uremic Syndrome Revisited in the Era of Complement Gene Mutations

Fakhouri¹,

Roumenina²,

François³

et al. 2010

Journal of the American Society of Nephrology

408

395

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In contrast to pregnancy-associated thrombotic thrombocytopenic purpura, the pathogenesis and presentation of pregnancy-associated atypical hemolytic uremic syndrome (P-aHUS) remain ill-defined. We conducted a retrospective study to assess the presentation and outcomes of patients presenting with P-aHUS and the prevalence of alternative C3 convertase dysregulation. P-aHUS occurred in 21 of the 100 adult female patients with atypical HUS, with 79% presenting postpartum. We detected complement abnormalities in 18 of the 21 patients. The outcomes were poor: 62% reached ESRD by 1 month and 76% by last follow-up. The risk for P-aHUS was highest during a second pregnancy. Thirty-five women, 26 (74%) of whom had complement abnormalities, had at least one pregnancy before the onset of a non-pregnancy-related aHUS. Outcomes did not differ between patients with pregnancy-related and non-pregnancy-related aHUS. Mutations in the SCR19-20 domains of factor H were less frequent in P-aHUS patients compared with non-pregnancy-related aHUS. Pregnancies in female patients with complement abnormalities (n ϭ 44) were complicated by fetal loss and preeclampsia in 4.8% and 7.7%, respectively. Better understanding of complement dysregulation in pregnancy complications is essential, especially to guide development of pharmacologic agents to modulate this system.

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Section: Methodsmentioning

confidence: 99%

Pregnancy-Associated Hemolytic Uremic Syndrome Revisited in the Era of Complement Gene Mutations

Fakhouri¹,

Roumenina²,

François³

et al. 2010

Journal of the American Society of Nephrology

408

395

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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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“…An interesting point is that approximately 90% of the MCP-aHUS patients are heterozygous, expressing 25-50% of the wild-type protein. Also, fH and MCP haplotypes, which predispose to this thrombomicroangiopathy, were identified in several large cohorts (Esparza-Gordillo et al, 2005;Fremeaux-Bacchi et al, 2005). The genes for fH and MCP are located at 1q32 in the regulators of complement activation (RCA) genetic cluster (Rodriguez de Cordoba et al, 1985).…”

Section: Introductionmentioning

confidence: 99%

Modeling how CD46 deficiency predisposes to atypical hemolytic uremic syndrome

Liszewski

Leung

Schraml

et al. 2007

Molecular Immunology

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Mutations in complement regulatory proteins predispose to the development of aHUS. Approximately 50% of patients bear a mutation in one of three complement control proteins, factor H, factor I, or membrane cofactor protein (MCP; CD46). Another membrane regulator that is closely related to MCP, decay accelerating factor (DAF; CD55) thus far has shown no association with aHUS and continues to be investigated. The goal of this study was to compare the regulatory profile of MCP and DAF and to assess how alterations in MCP predispose to complement dysregulation. We employed a model system of complement activation on Chinese hamster ovary (CHO) cell transfectants. The four regularly expressed isoforms of MCP and DAF inhibited C3b deposition by the alternative pathway. DAF, but not MCP, inhibited the classical pathway. Most patients with MCPaHUS are heterozygous and express only 25-50 % of the wild-type protein. We, therefore, analyzed the effect of reduced levels of wild-type MCP and found that cells with lowered expression levels were less efficient in inhibiting alternative pathway activation. Further, a dysfunctional MCP mutant, expressed at normal levels and identified in five patients with aHUS (S206P), failed to protect against C3b amplification on CHO cells, even if expression levels were increased 10-fold. Our results add new information relative to the necessity for appropriate expression levels of MCP and further implicate the alternative pathway in disease processes such as aHUS.

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The development of atypical haemolytic-uraemic syndrome is influenced by susceptibility factors in factor H and membrane cofactor protein: evidence from two independent cohorts

Cited by 161 publications

References 24 publications

Pregnancy-Associated Hemolytic Uremic Syndrome Revisited in the Era of Complement Gene Mutations

Pregnancy-Associated Hemolytic Uremic Syndrome Revisited in the Era of Complement Gene Mutations

Atypical Hemolytic Uremic Syndrome

Modeling how CD46 deficiency predisposes to atypical hemolytic uremic syndrome

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