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)

Although genetic defect of complement factor H (CFH) is a common cause of atypical hemolytic uremic syndrome (aHUS), development of autoantibodies to CFH (CFH-Ab) is also known to be an acquired cause of aHUS. Recently, a correlation between the development of CFH-Ab and the deficiency of the CFH-related proteins, CFHR1 and CFHR3, was identified. In this study, plasma complement profiles were measured and genetic analysis of the CFH, CFI, MCP, CFHR1, and CFHR3 genes were performed in three female patients diagnosed with aHUS with positive CFH-Ab. Acute stage plasmas of all the three patients revealed low C3, low or low-normal CFH antigenic levels, and high titers of CFH-Ab. All the patients also showed complete plasma CFHR1 deficiency and homozygous genomic deletion of CFHR1/CFHR3, but none had CFH, CFI, or MCP mutations. All the patients were treated with plasmapheresis, and two patients required additional immunosuppressive therapy. These patients had a novel subgroup of aHUS characterized by a combination of genetic (a homozygous deletion of CFHR1/CFHR3) and acquired (development of CFH-Ab) factors. Patients with this disease may need intensive immunosuppressive therapy in addition to plasmapheresis. Screening for CFH-Ab and the CFHR1/CFHR3 deficiency should be included in the diagnostic tests for patients with aHUS.
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PMID:Atypical hemolytic uremic syndrome associated with complement factor H autoantibodies and CFHR1/CFHR3 deficiency. 1953 76

Genetic studies have shown that mutations of complement inhibitors such as membrane cofactor protein, Factors H, I, or B and C3 predispose patients to atypical hemolytic uremic syndrome (aHUS). Factor I is a circulating serine protease that inhibits complement by degrading C3b and up to now only a few mutations in the CFI gene have been characterized. In a large cohort of 202 patients with aHUS, we identified 23 patients carrying exonic mutations in CFI. Their overall clinical outcome was unfavorable, as half died or developed end-stage renal disease after their first syndrome episode. Eight patients with CFI mutations carried at least one additional known genetic risk factor for aHUS, such as a mutation in MCP, CFH, C3 or CFB; a compound heterozygous second mutation in CFI; or mutations in both the MCP and CFH genes. Five patients exhibited homozygous deletion of the Factor H-related protein 1 (CFHR-1) gene. Ten patients with aHUS had one mutation in their CFI gene (Factor I-aHUS), resulting in a quantitative or functional Factor I deficiency. Patients with a complete deletion of the CFHR-1 gene had a significantly higher risk of a bad prognosis compared with those with one Factor I mutation as their unique vulnerability feature. Our results emphasize the necessity of genetic screening for all susceptibility factors in patients with aHUS.
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PMID:Mutations in components of complement influence the outcome of Factor I-associated atypical hemolytic uremic syndrome. 2011 98

Atypical hemolytic uremic syndrome (aHUS) is a rare disease of microangiopathic hemolytic anemia, thrombocytopenia, and predominant renal impairment. It is characterized by the absence of Shiga toxin-producing bacteria as a triggering factor. During the last decade, aHUS has been demonstrated to be a disorder of the complement alternative pathway dysregulation, as there is a growing list of mutations and polymorphisms in the genes encoding the complement regulatory proteins that alone or in combination may lead to aHUS. Approximately 60% of aHUS patients have so-called 'loss-of-function' mutations in the genes encoding the complement regulatory proteins, which normally protect host cells from complement activation: complement factor H (CFH), factor I (CFI) and membrane cofactor protein (MCP or CD46), or have 'gain-of-function' mutations in the genes encoding the complement factor B or C3. In addition, approximately 10% of aHUS patients have a functional CFH deficiency due to anti-CFH antibodies. Recent advances in understanding the pathogenesis of aHUS have led to a revised classification of the syndrome. Normal plasma levels of CFH and CFI do not preclude the presence of a mutation in these genes. Further, genotype-phenotype correlations of aHUS have clinical significance in predicting renal recovery and transplant outcome. Therefore, it is important to make a comprehensive analysis and perform genetic screening of the complement system in patients with aHUS to allow a more precise approach, especially before transplantation. This may also provide opportunities for more specific treatments in the near future, as complement inhibition could represent a therapeutic target in these patients who have a considerably poor prognosis in terms of both mortality and progression to end-stage renal disease and a great risk of disease recurrence after transplantation.
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PMID:Atypical hemolytic uremic syndrome: update on the complement system and what is new. 2009 Mar 63

Atypical hemolytic uremic syndrome (aHUS) is a disease characterized by overactivation of complement. Recurrence following renal transplantation is determined by a genetic predisposition. Genetic screening of all individuals with aHUS should be performed prior to listing for transplantation. Individuals with isolated mutations in MCP have a low risk of recurrence and may be considered for kidney transplantation alone. In individuals with CFH and CFI mutations, the risk of recurrence following renal transplantation is high. Combined liver/kidney transplantation has been used successfully in individuals with CFH mutations following the introduction of perioperative plasma exchange; however, such a procedure is not without its risks. Liver/kidney transplantation has yet to be performed on individuals with CFI and C3 mutations but may be predicted to be successful. In individuals with CFH autoantibodies, a reduction in titer through plasma exchange and rituximab has been successful. Clinical trials of the complement C5 inhibitor eculizumab may improve prospects for isolated renal transplantation in individuals with complement protein mutations.
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PMID:Transplantation in atypical hemolytic uremic syndrome. 2086 42

Thrombotic microangiopathies (TMAs) are pathological conditions characterized by generalized microvascular occlusion by platelet thrombi, thrombocytopenia, and microangiopathic hemolytic anemia. Two typical phenotypes of TMAs are hemolytic- uremic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP). Other disorders occasionally present with similar manifestations. Depending on whether renal or brain lesions prevail, two pathologically indistinguishable but somehow clinically different disorders have been described: HUS and TTP. Injury to the endothelial cell is the central and likely inciting factor in the sequence of events leading to TMA. Loss of physiological thromboresistance, leukocyte adhesion to damaged endothelium, complement consumption, abnormal von Willebrand factor release and fragmentation, and increased vascular shear stress may then sustain and amplify the microangiopathic process. Intrinsic abnormalities of the complement system and of the von Willebrand factor pathway may account for a genetic predisposition to the disease that may play a paramount role in particular in familial and recurrent forms. In the case of diarrhea-associated HUS (D+HUS), renal endothelial damage is mediated (at least in large part) by the bacterial agent Shigatoxin (Stx), which is actually a family of toxins elaborated by certain strains of Escherichia coli and Shigella dysenteriae. Outcome is usually good in childhood, Shiga toxin-associated HUS, whereas renal and neurological sequelae are more frequently reported in adult, atypical, and familial forms of HUS and in TTP. Recent studies have demonstrated that deficiency in the von Willebrand factor cleaving protease ADAMTS13, due to deficiency of ADAMTS13 can be genetic or more common, acquired, resulting from autoimmune production of inhibitory anti-ADAMTS13 antibodies, that causes TTP. During the last decade, atypical HUS (aHUS) has been demonstrated to be a disorder of the complement alternative pathway dysregulation, as there is a growing list of mutations and polymorphisms in the genes encoding the complement regulatory proteins that alone or in combination may lead to aHUS. Approximately 60% of aHUS patients have so-called 'loss-of-function' mutations in the genes encoding the complement regulatory proteins, which normally protect host cells from complement activation: complement factor H (CFH), factor I (CFI) and membrane cofactor protein (MCP or CD46), or have 'gain-of-function' mutations in the genes encoding the complement factor B or C3. In addition, approximately 10% of aHUS patients have a functional CFH deficiency due to anti-CFH antibodies. Although TMAs are highly heterogeneous pathological conditions, one-third of TMA patients have severe deficiency of ADAMTS13. Platelet transfusions are contraindicated. Plasma infusion or exchange (PE) is the only treatment of proven efficacy.
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PMID:Thrombotic microangiopathies: thrombotic thrombocytopenic purpura / hemolytic uremic syndrome. 2110 95

Hemolytic uremic syndrome (HUS) is a thrombotic microangiopathy (TMA) disorder characterised by the association of haemolytic anaemia, thrombocytopenia and acute renal failure. Atypical forms (non-shigatoxin related forms) may be familial or sporadic, frequently with relapses and most of them lead to end stage renal failure. During the last years, different groups have demonstrated genetic predisposition to atypical HUS (aHUS) involving five genes encoding for complement components which play a role in the activation or control of the alternative pathway: encoding factor H (CFH), accounting for 30% of aHUS; CD46 (encoding membrane cofactor protein [MCP]) accounting for approximately 10% of aHUS; CFI (encoding factor I) accounting for an estimated 5-15% of patients; C3 (encoding C3) accounting for approximately 10% of aHUS; and rarely CFB (encoding factor B). Predisposition to aHUS is inherited with incomplete penetrance. It is admitted that mutations confer a predisposition to develop aHUS rather than directly causing the disease and that a second event (genetic or environmental) is required for disease manifestation. HUS onset follows a triggering event in most cases (frequently banal seasonal infection and pregnancy). Uncontrolled C3 convertase leads to increased deposition of C3b on vascular endothelium and participates to the prothrombotic state. The phenotype of aHUS is variable ranging from mild forms, with complete recovery of renal function to severe forms with end stage renal disease within the first year after the onset. Overall, the outcome is severe with a mortality rate of 10% and with more than 60% of patients on dialysis. The most severe prognosis was in the CFH mutation group. There is a high risk of recurrence of the disease after renal transplantation in patients with mutations in CFH, CFI, CFB and C3. Plasma therapy may allow complete haematological remission but frequently with persistent renal damage. Some patients are plasma resistant and some are plasma dependent. The recent progress in the determination of the susceptibility factors for aHUS, have allowed to propose new diagnostic tests including a molecular genetic testing and may permit to consider some new specific treatments in this disease (human plasma-derived CFH or complement inhibitors).
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PMID:[Atypical hemolytic-uremic syndrome related to abnormalities within the complement system]. 2137 30

Atypical hemolytic uremic syndrome (aHUS) is a rare disease characterized by microangiopathic hemolytic anemia, thrombocytopenia, and acute renal failure. Mutations in genes encoding regulators of the alternative complement pathway (CFH, MCP, C3, CFI, CFB, THBD, and CFHR1-5) are connected with this disease. Polymorphisms (SNPs) in these genes might also influence the manifestation of aHUS. We have analyzed the genes of CFH, CFI, MCP, and C3 in a cohort of 10 unrelated Czech patients with clinically diagnosed familial aHUS. Surprisingly, 4 patients had mutations only in MCP, without mutations in any of the other genes that cause aHUS. Mutations, as yet unpublished, were widely distributed over the gene (SCR2 domain, signal peptide, and cytoplasmic region). The phenotype of the patients and their close relatives (14 individuals) was also investigated. Functional examination of MCP was also provided and proved lower expression on granulocytes in all mutations. Severity of disease varied, but onset was never earlier than 5 years of age. Penetrance of disease was 50% among carriers. We found that the severity and recurrence of the disease within families varied and might also be dependent on SNPs. Mutations in the MCP gene seems to be a common etiology of aHUS in Czech patients.
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PMID:Manifestation of atypical hemolytic uremic syndrome caused by novel mutations in MCP. 2170 48

Atypical hemolytic uremic syndrome (aHUS) is a severe renal disorder that is associated with mutations in genes encoding proteins of the alternative complement pathway. Previously, we identified pathogenic variations in genes encoding complement regulators (CFH, CFI and MCP) in our aHUS cohort. In this study, we screened for mutations in the alternative pathway regulator CFHR5 in 65 aHUS patients by means of PCR on genomic DNA and sequence analysis. Potential pathogenicity of genetic alterations was determined by published data on CFHR5 variants, evolutionary conservation and in silico mutation prediction programs. Detection of serum CFHR5 was performed by western blot analysis and enzyme-linked immunosorbent assay. A potentially pathogenic sequence variation was found in CFHR5 in three patients (4.6%). All variations were located in short consensus repeats that might be involved in binding to C3b, heparin or C-reactive protein. The identified CFHR5 mutations require functional studies to determine their relevance to aHUS, but they might be candidates for an altered genetic profile predisposing to the disease.
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PMID:Atypical hemolytic uremic syndrome and genetic aberrations in the complement factor H-related 5 gene. 2273 21

Several abnormalities in complement genes reportedly contribute to atypical hemolytic uremic syndrome (aHUS), but incomplete penetrance suggests that additional factors are necessary for the disease to manifest. Here, we sought to describe genotype-phenotype correlations among patients with combined mutations, defined as mutations in more than one complement gene. We screened 795 patients with aHUS and identified single mutations in 41% and combined mutations in 3%. Only 8%-10% of patients with mutations in CFH, C3, or CFB had combined mutations, whereas approximately 25% of patients with mutations in MCP or CFI had combined mutations. The concomitant presence of CFH and MCP risk haplotypes significantly increased disease penetrance in combined mutated carriers, with 73% penetrance among carriers with two risk haplotypes compared with 36% penetrance among carriers with zero or one risk haplotype. Among patients with CFH or CFI mutations, the presence of mutations in other genes did not modify prognosis; in contrast, 50% of patients with combined MCP mutation developed end stage renal failure within 3 years from onset compared with 19% of patients with an isolated MCP mutation. Patients with combined mutations achieved remission with plasma treatment similar to patients with single mutations. Kidney transplant outcomes were worse, however, for patients with combined MCP mutation compared with an isolated MCP mutation. In summary, these data suggest that genotyping for the risk haplotypes in CFH and MCP may help predict the risk of developing aHUS in unaffected carriers of mutations. Furthermore, screening patients with aHUS for all known disease-associated genes may inform decisions about kidney transplantation.
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PMID:Combined complement gene mutations in atypical hemolytic uremic syndrome influence clinical phenotype. 2343 Oct 77

C3 glomerulopathy is a recent disease classification comprising several rare types of glomerulonephritis, including dense deposit disease (DDD) and C3 glomerulonephritis (C3GN). The most common histological feature in these diseases is the presence of glomerular deposition of C3 within the mesangium and along the glomerular basement membrane (GBM) in the subendothelial area or within the GBM. The key role of complement alternative pathway (AP) in these disorders has been recently shown with the identification of acquired or genetic abnormalities. Low serum C3 level but normal C4 is a common finding. The acquired AP dysregulation in DDD and C3GN may be first induced by C3 nephritic factor (C3NeF). C3NeF activity is found in approximately 80% of patients with DDD and in 45% of patients with C3GN. The correlation with the complement is further supported by the detection of homozygous or heterozygous mutations in the regulatory complement proteins factor H (CFH), factor I (CFI), or C3. The genetic background of the patients may also influence the disease manifestation since common genetic variants including single nucleotide polymorphisms in the CFH, C3 and CFHR5 genes are associated with DDD and one at-risk MCP haplotype have been found to be significantly increased in C3GN. C3 glomerulopathies can present over a broad age range. DDD is more often diagnosed in children and age at diagnosis is significantly higher for patients with C3GN. Presenting features comprise any of proteinuria, hematuria, hypertension and renal failure. These glomerulonephritides are associated with chronic deterioration of renal function, leading to ESRD within 10 years of the diagnosis in 36-50% of patients. Outcomes of renal transplantation are characterized by histological recurrence which may contribute to increased rates of allograft failure. Administration of recombinant FH if it becomes available or replacement of FH via plasma exchange may be efficacious in the cases of FH deficiency. However, therapeutic inhibition of complement C3 and C5 is the main perspective.
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PMID:C3 glomerulopathy. 2368 80


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