182 research outputs found
Inherited dysregulation of the complement system
No full textIn recent years there has been a substantial increase in the understanding of the genetics and pathogenesis of HUS. Mutations in factor H, a fluid-phase regulator of the alternative complement pathway, have been identified in 15-30% of patients with both familial and sporadic (D-) HUS. The mutations mainly cluster in the C terminal part of factor H, a region that is important for both binding to c3b and also polyanionic structures on cell surfaces. This leads to loss of protection against complement mediated endothelial injury. Mutations in the membrane bound complement regulator, membrane cofactor protein (MCP; CD46) have also been described in three families. These result in an impairment of inactivation of surface bound c3b. Finally mutations in the serine protease, factor I that lead to deficiency of the protein have been reported in two HUS patients. There is therefore now overwhelming evidence that dysregulation of the alternative complement pathway predisposes to the development of a thrombotic microangiopath
Factor H genotype-phenotype correlations: Lessons from aHUS, MPGN II, and AMD
No full textMissense mutations in the C-terminal region of Factor H are associated with atypical hemolytic uremic syndrome, whereas homozygous Factor H deficiency is more frequently associated with membranoproliferative glomerulonephritis type II (MPGN II). The report of Licht et al. of a mutation in the complement- regulatory N-terminal region of Factor H in MPGN II provides additional insight into the pathogenesis of this condition
Molecular modelling of the C-terminal domains of factor H of human complement: A correlation between haemolytic uraemic syndrome and a predicted heparin binding site
No full textFactor H (FH) of the complement system acts as a regulatory cofactor for the factor I-mediated cleavage of C3b and binds to polyanionic substrates. FH is composed of 20 short consensus/complement repeat (SCR) domains. A set of 12 missense mutations in the C-terminal domains between SCR-16 to SCR-20 is associated with haemolytic uraemic syndrome. Recent structural models for intact FH permit the molecular interpretation of these amino acid substitutions. As all nine SCR-20 substitutions correspond to normal amounts of FH in plasma, and were localised in mostly surface-exposed positions, these are inferred to lead to a functional defect in FH. The nine substitutions occur in the same spatial region of SCR-20. As this surface coincides with conserved basic residues in the C-terminal SCR-20 domain, the substitutions provide direct evidence for a polyanionic binding surface. The positions of these conserved basic residues coincide with those of heparin-binding residues in the crystal structure of the acidic fibroblast growth factor-heparin complex. A tenth substitution and another conserved basic residue in SCR-19 are proximate to this binding site. As the remaining FH substitutions could also be correlated with their proximity to conserved basic residues, haemolytic uraemic syndrome may result from a failure of FH to interact with polyanions at cell surfaces in the kidney. \ua9 2002 Elsevier Science Ltd
Atypical hemolytic uremic syndrome
No full textPurpose of review The last few years revealed a molecular distinction between thrombotic thrombocytopenic purpura, a disease characterized by a lack of ADAMTS13 activity, and atypical hemolytic uremic syndrome (aHUS), a disease of complement overactivation. Many different predisposing genetic factors resulting in complement overactivation have been described in aHUS. Additionally, autoantibodies against complement regulatory proteins have been reported. Recent findings The last year has seen the description of a new risk factor for aHUS in the form of mutations in thrombomodulin. As with other genetic risk factors seen in aHUS, these mutations result in impaired regulation of complement. It is increasingly recognized that a confluence of risk factors resulting in complement overactivation may be required for the disease to manifest. In the last year the complement inhibitor eculizumab has been used successfully to treat patients with aHUS. Summary The characterization of the molecular defect in aHUS has allowed targeted therapy to be used. Although early reports of the efficacy of the complement inhibitor eculizumab are promising, the outcome of a recent clinical trial is awaited
Membrane cofactor protein and factor I: Mutations and transplantation
No full textMutations in the genes for three complement regulators-complement factor H (CFH), membrane cofactor protein (MCP), and factor I (IF)-have now been described in patients with atypical HUS. The functional effects of these mutations have been studied in detail and have been shown to affect secretion, expression, and regulatory function. Genotype-phenotype correlations have shown that the majority of patients with CFH, MCP, and FI mutations develop end-stage renal failure. The outcome of transplantation is poor in patients known to have either a CFH or FI mutation, with approximately 80% of patients losing the graft to recurrent disease within 2 years. In contrast, patients known to have only an MCP mutation have a satisfactory transplantation outcome. This is expected because MCP is a transmembrane regulator and allografts will therefore be protected by wild-type MCP. Combined liver/kidney transplantation for patients known to have a CFH mutation has not been successful to date. There is optimism that in the future, targeted complement inhibitors will be of major therapeutic benefit in this condition. Copyright \ua9 2006 by Thieme Medical Publishers, Inc
Atypical haemolytic uraemic syndrome
No full textThe haemolytic uraemic syndrome (HUS) is characterized by the triad of thrombocytopenia, microangiopathic haemolytic anaemia and acute renal failure. HUS may be classified as either diarrhoeal-associated or non-diarrhoeal/atypical (aHUS). aHUS has recently been shown to be a disease of complement dysregulation, with 50% of cases involving the complement regulatory genes, factor H (CFH), membrane cofactor protein (MCP; CD46), and factor I (IF). However, incomplete penetrance of mutations in each of these genes is reported. This suggests that a precipitating event or trigger is required to unmask the complement regulatory deficiency. The reported precipitating events predominantly cause endothelial injury. Discovery of these mutations has revealed important genotype-phenotype correlations. MCP-HUS has a better prognosis and a better outcome after transplantation than either CFH-HUS or IF-HUS. \ua9 The Author 2006
- …
