Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.4.25.1 (proteasome)
28,817 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Two human neuroblastoma cell lines activated the classical pathway of complement in serum. Activation caused the opsonisation of these cells with complement fragments but with moderate cell killing. Neuroblastoma expressed regulators MCP and CD59 but did not express DAF or CR1. Neutralisation of CD59 rendered the cells susceptible to killing. Neuroblastoma also expressed C1-inhibitor, factor H, clusterin and S-protein. Expression of several regulators was enhanced by incubation with cytokines. Complement inhibition using soluble CRI markedly reduced opsonisation and killing of neuroblastoma. Our results suggest that complement might play a role in neuronal loss and that treatment with complement inhibitors might be of therapeutic value.
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PMID:Complement activation on human neuroblastoma cell lines in vitro: route of activation and expression of functional complement regulatory proteins. 896 11

C4b and C3b deposited on host cells undergo limited proteolytic cleavage by regulatory proteins. Membrane cofactor protein (MCP; CD46), factor H, and C4b binding protein mediate this reaction, known as cofactor activity, that also requires the plasma serine protease factor I. To explore the roles of the fluid phase regulators vs those expressed on host cells, a model system was used examining complement fragments deposited on cells transfected with human MCP as assessed by FACS and Western blotting. Following incubation with Ab and complement on MCP(+) cells, C4b was progressively cleaved over the first hour to C4d and C4c. There was no detectable cleavage of C4b on MCP(-) cells, indicating that MCP (and not C4BP in the serum) primarily mediates this cofactor activity. C3b deposition was not blocked on MCP(+) cells because classical pathway activation occurred before substantial C4b cleavage. Cleavage, though, of deposited C3b was rapid (<5 min) and iC3b was the dominant fragment on MCP(-) and MCP(+) cells. Studies using a function-blocking mAb further established factor H as the responsible cofactor. If the level of Ab sensitization was reduced 8-fold or if Mg(2+)-EGTA was used to block the classical pathway, MCP efficiently inhibited C3b deposition mediated by the alternative pathway. Thus, for the classical pathway, MCP is the cofactor for C4b cleavage and factor H for C3b cleavage. However, if the alternative pathway mediates C3b deposition, then MCP's cofactor activity is sufficient to restrict complement activation.
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PMID:Role of membrane cofactor protein (CD46) in regulation of C4b and C3b deposited on cells. 1205 45

Membrane cofactor protein (MCP; CD46) is a widely expressed transmembrane complement regulator. Like factor H it inhibits complement activation by regulating C3b deposition on targets. Factor H mutations occur in 10-20% of patients with hemolytic uremic syndrome (HUS). We hypothesized that MCP mutations could predispose to HUS, and we sequenced MCP coding exons in affected individuals from 30 families. MCP mutations were detected in affected individuals of three families: a deletion of two amino acids (D237/S238) in family 1 (heterozygous) and a substitution, S206P, in families 2 (heterozygous) and 3 (homozygous). We evaluated protein expression and function in peripheral blood mononuclear cells from these individuals. An individual with the D237/S238 deletion had reduced MCP levels and approximately 50% C3b binding compared with normal controls. Individuals with the S206P change expressed normal quantities of protein, but demonstrated approximately 50% reduction in C3b binding in heterozygotes and complete lack of C3b binding in homozygotes. MCP expression and function was evaluated in transfectants reproducing these mutations. The deletion mutant was retained intracellularly. S206P protein was expressed on the cell surface but had a reduced ability to prevent complement activation, consistent with its reduced C3b binding and cofactor activity. This study presents further evidence that complement dysregulation predisposes to development of thrombotic microangiopathy and that screening patients for such defects could provide informed treatment strategies.
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PMID:Mutations in human complement regulator, membrane cofactor protein (CD46), predispose to development of familial hemolytic uremic syndrome. 1456 51

Membrane cofactor protein (MCP, CD46) is a widely expressed transmembrane complement regulator. As does the soluble regulator factor H, it inhibits complement activation by inactivating the C3b that is deposited on target membranes. Factor H mutations have been described in 15-30% of patients with atypical haemolytic uraemic syndrome (HUS). Recent studies have identified mutations in the MCP gene in four families. In one, a heterozygous deletion resulted in the intracellular retention of the mutant protein. In another, a different heterozygous deletion led to a premature stop codon and the loss of the C-terminus. In the other two, a substitution (S206P) resulted in cell-surface expression but inefficient inactivation of surface-bound C3b. These findings provide further evidence that complement dysregulation predisposes to the development of HUS.
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PMID:Mutations in CD46, a complement regulatory protein, predispose to atypical HUS. 1512 Oct 49

In 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 microangiopathy.
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PMID:Inherited dysregulation of the complement system. 1561 93

The efficiency of the complement system as an innate immune defense mechanism depends on a fine control that restricts its action to pathogens and prevents non-specific damage to host tissues. Genetic and functional analyses have shown that this critical control of complement activation may be impaired in atypical hemolytic uremic syndrome (aHUS) patients. Mutations in HF1, MCP or FI have been found in aHUS patients, but incomplete penetrance of the disease in individuals carrying these mutations is relatively frequent and no genetic defect has yet been found in a majority of aHUS patients. We report here the identification of a specific SNP haplotype block, spanning the MCP gene in the regulators of complement activation gene cluster, which is over-represented in aHUS patients and strongly associates with the severity of the disease. Linkage disequilibrium analyses suggest that this SNP haplotype also includes the CR1, DAF and C4BP genes. Initial studies identified two SNPs in the haplotype that influence the transcription activity of the MCP promoter in transient transfection experiments. Notably, the SNP haplotype block was found to be particularly frequent among patients who carry mutations in HF1, MCP or FI. These findings and the identification of aHUS patients carrying mutations in two complement regulatory genes provide an important insight into the etiology of aHUS. Together, they suggest that complement regulatory molecules act as a protein network and that multiple hits, involving plasma- and membrane-associated complement regulatory proteins, are necessary to impair protection to host tissues and to confer significant predisposition to aHUS.
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PMID:Predisposition to atypical hemolytic uremic syndrome involves the concurrence of different susceptibility alleles in the regulators of complement activation gene cluster in 1q32. 1566 53

Hemolytic uremic syndrome (HUS) is a disease characterized by non immune hemolytic anemia, low platelet count and renal impairment. In children, the disease is most commonly triggered by Shiga-like toxin (Stx)-producing Escherichia coli (Stx-E. Coli): however, renal function recovers in up to 70% of patients. Plasma infusion or exchange reduces mortality and the risk of end-stage renal disease (ESRD) in adult patients. Non-Shiga toxin-associated HUS (non-Stx-HUS), accounting for only 5-10% of all disease cases, can be sporadic or familial. Collectively, non-Stx-HUS forms have a poor outcome. Up to 50% of cases progress to ESRD or have irreversible brain damage, and 25% can die during the acute phase of the disease. Genetic studies have recently documented that the familial form is associated with genetic abnormalities of complement regulatory proteins, and evidence is now emerging that similar genetic alterations can predispose to sporadic cases of non-Stx-HUS as well. Mutations of genes encoding for factor H, a glycoprotein that plays an important role in the regulation of the alternative pathway of complement and for MCP, a widely expressed transmembrane glycoprotein with an inhibitory role of activated C3, are reported in familial HUS. These mutations are more likely to predispose rather than to cause the disease directly.
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PMID:[Hemolytic uremic syndrome]. 1641 8

HEMOLYTIC UREMIC SYNDROME POST-PARTUM: We describe a case of a 37-year-old woman admitted for severe renal failure to our hospital immediately after the delivery by caesarean section of twins. She had anuria, anemia, and moderate thrombocytopenia. A diagnosis of hemolytic-uremic syndrome was made. Plasma exchange was started, substitution was performed with fresh frozen plasma and eight consecutive plasmapheresis sessions were given. She received hydrocortisone and ACE inhibitors. After about fifteen days from the beginning of the illness, signs of active haemolysis disappeared and renal function was partially recovered. A genetic study demonstrated the absence of HF1 and MCP mutations but a polymorphic variant of the HF1 gene (C-257T promoter region). This polymorphism is strongly associated with non-diarrhoea-HUS (D-HUS). Post-partum HUS is quite a rare syndrome and has a poor outcome; however prompt diagnosis and efficacious therapy could save lives without clinical consequences. The excellent outcome of this patient seems to corroborate this concept.
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PMID:A post-partum hemolytic-uremic-like-syndrome in a patient with pre-eclampsia: description of a clinical case. 1642 9

Atypical hemolytic uremic syndrome (HUS) is a severe disease that is characterized by microangiopathic hemolytic anemia, thrombocytopenia, and acute renal failure. Recent evidence has shown that defective complement activation and defective complement control is a cause of HUS. So far, mutations in single genes coding for the cofactor and complement regulator factor H, the membrane cofactor protein (MCP/CD46), the serine protease factor I, and autoantibodies to factor H have been linked to HUS. All of these proteins affect the same enzyme the alternative pathway convertase C3bBb. This article explains how alternative pathway activation proceeds and how defective control increases activation, which ultimately leads to endothelial cell damage.
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PMID:The role of defective complement control in hemolytic uremic syndrome. 1657 89

Hemolytic uremic syndrome (HUS) is characterized by the triad of thrombocytopenia, microangiopathic hemolytic anemia, and acute renal failure. The non-Shiga toxin-associated HUS (atypical HUS [aHUS]) has been shown to be a disease of complement dysregulation. Mutations in the plasma complement regulators factor H and factor I and the widely expressed membrane cofactor protein (MCP; CD46) have been described recently. This study looked for MCP mutations in a panel of 120 patients with aHUS. In this cohort, approximately 10% of patients with aHUS (11 patients; nine pedigrees) have mutations in MCP. The onset typically was in early childhood. Unlike patients with factor I or factor H mutations, most of the patients do not develop end-stage renal failure after aHUS. The majority of patients have a mutation that causes reduced MCP surface expression. A small proportion expressed normal levels of a dysfunctional protein. As in other studies, incomplete penetrance is shown, suggesting that MCP is a predisposing factor rather than a direct causal factor. The low level of recurrence of aHUS in transplantation in patients with MCP mutations is confirmed, and the first MCP null individuals are described. This study confirms the association between MCP deficiency and aHUS and further establishes that a deficiency in complement regulation, specifically cofactor activity, predisposes to severe thrombotic microangiopathy in the renal vasculature.
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PMID:Genetic and functional analyses of membrane cofactor protein (CD46) mutations in atypical hemolytic uremic syndrome. 1679 May 5


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