Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0002878 (hemolytic anemia)
 7,530 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Haemolytic uraemic syndrome (HUS) is a thrombotic microangiopathy (TMA) disorder characterised by the association of haemolytic anaemia, thrombocytopenia and acute renal failure. Atypical forms (non-related to shigatoxin) may be familial or sporadic, with frequent recurrences and most of them lead to end stage renal failure. During the last years, different groups have demonstrated genetic predisposition of atypical HUS involving complement components factor H (FH), CD46 [or membrane co-factor protein (MCP)] and factor I. These three proteins are involved in the regulation of the alternative pathway of the complement system. Several series have reported mutations in the FH gene (called HF1) in between 10 and 22% of atypical HUS patients. At this time, four pedigrees corresponding to 13 cases have been reported with an MCP mutation and four cases with a sporadic disease presented factor I mutation. Whereas FH mutations were reported in both familial and sporadic forms of HUS, CD46 mutations were restricted to familial HUS, and factor I mutations were only observed in cases of sporadic HUS. We speculate that the penetrance of the disease may be variable regarding the identified susceptibility factors. Recently, the analysis of single nucleotide polymorphisms in both HF1 and MCP in three large cohorts of HUS patients identified significant association between atypical HUS and HF1 and MCP particular alleles. All these results, together with the finding of anti-FH antibodies in some atypical HUS patients, strongly suggest that an abnormality in the regulation of the alternative pathway participates in the patho-physiological mechanisms of atypical HUS. The recent progress made in the determination of susceptibility factors for atypical HUS has permitted the development of new diagnostic tests and may eventually lead to new specific treatments to block the pathological process.
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PMID:Atypical haemolytic uraemic syndrome and mutations in complement regulator genes. 1618 52

Hemolytic uremic syndrome (HUS) is a triad of microangiopathic hemolytic anemia, thrombocytopenia, and acute renal failure. HUS is classified as either diarrhea associated, most commonly caused by infection with Escherichia coli O157, or the less common atypical HUS (aHUS), which may be familial or sporadic. Approximately 50% of patients with aHUS have mutations in one of the complement control proteins: factor H, factor I, or membrane cofactor protein (MCP). These proteins regulate complement activation through cofactor activity, the inactivation of C3b by limited proteolytic cleavage, a desirable event in the fluid phase (no target) or on healthy self-tissue (wrong target). Complement activation follows the endothelial cell injury that characterizes HUS. This disease represents a model of what takes place when inappropriate complement activation occurs on self-tissues due to the presence of mutated complement regulatory proteins. Screening for mutations in factor H, factor I, or MCP is expensive and time consuming. One approach is to perform antigenic screening for factor H and factor I deficiency and to look for low levels of MCP (CD46) expression by flow cytometry. Complement regulatory protein deficiency impacts treatment decisions as patients with aHUS have a recurrence rate in renal transplants of approximately 50%, whereas those with factor H mutations have an even higher risk (approximately 80%). By contrast, MCP deficiency can be corrected in part by a renal allograft. However, caution in the use of live-related donations is needed because of the high rates of incomplete penetrance of the described mutations.
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PMID:Hemolytic uremic syndrome: an example of insufficient complement regulation on self-tissue. 1638 83

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

The hemolytic uremic syndrome is characterized by the triad of microangiopathic hemolytic anemia, thrombocytopenia and acute renal failure. There are two general types. One occurs in epidemic form and is diarrheal associated (D+HUS). It has a good prognosis. The second is a rare form known as atypical (aHUS), which may be familial or sporadic, and has a poor prognosis. aHUS is increasingly recognized to be a disease of defective complement regulation, particularly cofactor activity. Mutations in membrane cofactor protein (MCP; CD46) that predispose to the development of aHUS were first identified in 2003. MCP is a membrane-bound complement regulator that acts as a cofactor for the factor I-mediated cleavage of C3b and C4b deposited on host cells. More than 20 different mutations in MCP have now been identified in patients with aHUS. Many of these mutants have been functionally characterized and have helped to define the pathogenic mechanisms leading to aHUS development. Over 75% of the reported mutations cause a reduction in MCP expression, due to homozygous, compound heterozygous or heterozygous mutations. This deficiency of MCP leads to inadequate control of complement activation on endothelial cells after an initiating injury. The remaining MCP mutants are expressed, but demonstrate reduced ligand (C3b/C4b) binding capacity and cofactor activity of MCP. MCP mutations in aHUS demonstrate incomplete penetrance, indicating that additional genetic and environmental factors are required to manifest disease. MCP mutants as a cause of aHUS have a favorable clinical outcome in comparison to patients with factor H (CFH) or factor I (IF) mutations. In 90% of the renal transplants performed in patients with MCP-HUS, there has been no recurrence of the primary disease, whilst >50% of factor I or factor H deficient patients have had a prompt recurrence. This highlights the importance of defining and characterizing the underlying genetic defects in patients with aHUS.
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PMID:Implications of the initial mutations in membrane cofactor protein (MCP; CD46) leading to atypical hemolytic uremic syndrome. 1688 52

The 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.
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PMID:Atypical haemolytic uraemic syndrome. 1696 92

Several mutations in the CFH gene have been described in non-Shiga-toxin-associated haemolytic uraemic syndrome (non-Stx-HUS), a rare syndrome characterized by haemolytic anaemia, thrombocytopenia and acute renal failure. Mutations in genes encoding other complement regulatory proteins, membrane cofactor protein (CD46) and complement factor I (CFI), were also involved in the pathogenesis of the disease. Anyway, mutations in the three genes account for no more than 50% of cases of non-Stx-HUS. Human complement factor H related 5 (CFHR5) is a recently characterised member of the human complement factor H (CFH) family that has been found as a component of immune deposits in human kidney with sclerotic lesions from different causes. CFHR5 possesses cofactor activity and has been proposed to play a role in complement regulation in the glomerulus. We screened CFHR5 gene for variations potentially involved in the aetiology of HUS. Forty-five patients with HUS and 80 controls were analysed. Altogether, 5 genetic variants in CFHR5 were found in overall 9/45 HUS patients and in 4/80 controls. Statistical analysis showed that allelic variants in CFHR5 were prefentially associated with HUS. Based on these data, we conclude that, though not causative, CFHR5 genetic alterations may play a secondary role in the pathogenesis of HUS.
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PMID:Genetic analysis of the complement factor H related 5 gene in haemolytic uraemic syndrome. 1700

Hemolytic uremic syndrome is a triad of microangiopathic hemolytic anemia, thrombocytopenia, and acute renal failure. It is one of a group of conditions termed the thrombotic microangiopathies, which are characterized by prominent endothelial cell injury. It may be diarrheal-associated or atypical (aHUS). Evidence for a pathogenic role of the alternative pathway of complement was first suggested in 1974. Mutations in the complement regulatory proteins factor H, membrane cofactor protein (CD46), and factor I predispose to aHUS development. Mutations of the activating components factor B and complement C3 have also been reported. Penetrance is approximately 50%, suggesting other genetic and environmental modifiers are needed for disease expression. Identification of mutations is important owing to differences in mortality, renal survival, and outcome of renal transplantation. Current treatment is plasma infusion/exchange, but complement inhibitor therapy provides hope for the future.
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PMID:Complement regulatory genes and hemolytic uremic syndromes. 1770 84

The hemolytic uremic syndrome (HUS) is a triad of microangiopathic hemolytic anemia, thrombocytopenia, and renal impairment. Genetic studies demonstrate that heterozygous mutations of membrane cofactor protein (MCP;CD46) predispose to atypical HUS (aHUS), which is not associated with exposure to Shiga toxin (Stx). Among the initial 25 MCP mutations in patients with aHUS were 2, R69W and A304V, that were expressed normally and for which no dysfunction was found. The R69W mutation is in complement control protein module 2, while A304V is in the hydrophobic transmembrane domain. In addition to 3 patients with aHUS, the A304V mutation was identified in 1 patient each with fatal Stx-HUS, the HELLP (hemolysis, elevated liver enzymes, and low platelets) syndrome, and glomerulonephritis with C3 deposits. A major goal was to assess if these putative mutations lead to defective complement regulation. Permanent cell lines expressing the mutated proteins were complement "challenged," and membrane control of C3 fragment deposition was monitored. Both the R69W and A304V MCP mutations were deficient in their ability to control the alternative pathway of complement activation on a cell surface, illustrating the importance of modeling transmembrane proteins in situ.
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PMID:Membrane cofactor protein mutations in atypical hemolytic uremic syndrome (aHUS), fatal Stx-HUS, C3 glomerulonephritis, and the HELLP syndrome. 1791 26

We report the first cases of atypical hemolytic and uremic syndrome associated with complement factor H (CFH) deficiency in native kidneys and glomerulonephritis with isolated C3 deposits after kidney transplantation. Two boys developed atypical hemolytic and uremic syndrome at 16 and 11 months of age, associated with low C3 and CFH levels. Both rapidly progressed to end-stage renal failure and received a kidney transplant. Patient 1 had combined CFH and complement factor I (CFI) heterozygous mutations and a membrane cofactor protein (gene symbol, CD46) gene polymorphism. Five years posttransplantation, an allograft biopsy specimen showed numerous mesangial and extramembranous C3 deposits, although the patient had no biological sign of glomerulopathy. Nine years after transplantation, he was well with stable kidney function. Patient 2, who had a homozygous CFH mutation, developed glomerulonephritis with isolated C3 deposits 5 months after kidney transplantation while he was treated for early recurrence of hemolytic anemia. Four years later, the second kidney transplant biopsy specimen showed recurrence of thrombotic microangiopathy. Six years posttransplantation, kidney function was stable and complete blood cell count was normal with regular plasma therapy. These observations suggest that constitutional dysregulation of the alternative pathway is associated with a wide spectrum of kidney diseases, and glomerulonephritis with isolated C3 deposits and thrombotic microangiopathy may be different expressions of the same condition. Several factors could influence the disease, such as degree of CFH haploinsufficiency and other complement alternative pathway regulator abnormalities, such as a membrane cofactor protein polymorphism.
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PMID:Complement factor H deficiency and posttransplantation glomerulonephritis with isolated C3 deposits. 1837 43


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