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)

The spectrum of the thrombotic microangiopathies (TMA) encompasses a heterogeneous group of disorders with hereditary and acquired forms. Endothelial cell injury in the microvasculature is common to all TMAs, whatever the pathophysiological process. In this review we describe genetic mutations characteristic of certain TMAs and review their contributions to disease. Recent identification of novel pathologic mutations has been enabled by exome studies. The monogenic forms of TMA are more frequently caused by recessive alterations in von Willebrand factor cleaving protease ADAMST13, leading to congenital thrombotic thrombocytopenic purpura, or cobalamine C and DGKE genes, leading to an atypical hemolytic-uremic syndrome (aHUS)-like TMA. aHUS, whether idiopathic or linked to a known complement amplifying condition, is a TMA that primarily affects kidney function. It often results from a combination of an underlying genetic susceptibility with environmental factors activating the alternative complement pathway. Pathogenic variants in at least five complement genes coding for complement factor H (CFH) complement factor I (CFI), MCP (CD46), C3 and complement factor B (CFB) have been demonstrated to increase the risk of developing aHUS, but several more genes have been implicated. A new challenge is to separate disease-associated genetic variants from the broader background of variants or polymorphisms present in all human genomes that are rare, potentially functional, but may or may not be pathogenic.
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PMID:Defining the genetics of thrombotic microangiopathies. 2717 91

: We bring the case of a 38-year-old man who was presented to the emergency department with nausea, fever, and choluria, 4 days after the ingestion of raw oysters. Analytical study revealed thrombocytopenia and acute kidney injury that were associated to a possible thrombotic microangiopathy. Therapeutic plasma exchange was started and resolution of the manifestations was obtained. To identify the cause of the thrombotic microangiopathy a molecular study was performed and a pathogenic variant in the MCP gene, c.287-2A>G (splice acceptor) in heterozygous state with a concomitant presence of both risk haplotypes, MCPggaac and Complement factor H (CFH)-H3 were identified. These findings make the diagnosis of atypical hemolytic-uremic syndrome (aHUS), and despite a relatively benign course with a positive response to plasma exchange without an evolution to renal failure was evident a recurrent profile of aHUS when associated with an infectious trigger.
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PMID:Atypical hemolytic-uremic syndrome: recurrent phenotypic expression of a patient with MCP gene mutation combined with risk haplotypes. 3067 36

Atypical hemolytic uremic syndrome (aHUS) is a heterogeneous disorder characterized by microangiopathic hemolytic anemia (MAHA), thrombocytopenia, and acute kidney injury (AKI). In about 50% of cases, pathogenic variants in genes involved in the innate immune response including complement factors complement factor H (CFH), CFI, CFB, C3, and membrane co-factor protein (MCP/CD46) put patients at risk for uncontrolled activation of the alternative complement pathway. As aHUS is characterized by incomplete penetrance and presence of additional triggers for disease manifestation, genetic variant interpretation is challenging and streamlined functional variant evaluation is urgently needed. Here, we report the case of a 27-year-old female without previous medical and family history who presented with confusion, petechial bleeding, and anuric AKI. Kidney biopsy revealed glomerular thrombotic microangiopathy (TMA). Targeted next generation sequencing identified a paternally transmitted novel heterozygous splice site variant in the CFH gene [c.3134-2A>G; p.Asp1045_Thr1053del] which resulted in a partial in-frame deletion of exon 20 transcript as determined by cDNA analysis. On the protein level, the concomitant loss of 9 amino acids in the short consensus repeat (SCR) domains 17 and 18 of CFH includes a highly conserved cysteine residue, which is assumed to be essential for proper structural folding and protein function. Treatment with steroids, plasmapheresis, and the complement inhibitor eculizumab led to complete hematological and clinical remission after several months and stable renal function up to 6 years later. In conclusion, genetic investigation for pathogenic variants and evaluation of their functional impact, in particular in the case of splice site variants, is clinically relevant and enables not only better molecular understanding but helps to guide therapy with complement inhibitors.
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PMID:Deleterious Impact of a Novel CFH Splice Site Variant in Atypical Hemolytic Uremic Syndrome. 3115 13

Haemolytic uraemic syndrome (HUS) is most commonly associated with Shiga toxin-producing Escherichia coli (STEC) while the recurrent hereditary atypical (aHUS) form secondary to complement system control protein mutations is relatively rare. A 6-year-old boy with complement factor H (CFH) and factor B (CFB) mutations and a history of bloody diarrhoea and PCR positivity for Shiga toxin was initially diagnosed as STEC+HUS. Acute kidney injury resolved with Eculizumab but he remains with chronic renal failure. Although the exact role of STEC in the pathogenesis of aHUS in this patient is not certain, there seems to be a relationship. However, several issues remain to be explained including the effect of genetic and environmental factors in modifying susceptibility to develop aHUS in some patients following STEC infection.Abbreviations: aHUS: atypical haemolytic uraemic syndrome; ANA: anti-nuclear antibody; ANCA: anti-neutrophil cytoplasmic antibody; ASO: anti-streptolysin O; BUN: blood urea nitrogen; CFB: complement factor B; CFH: complement factor H; EHEC: enterohaemorrhagic Escherichia coli; MCP: membrane co-factor protein; PD: peritoneal dialysis; STEC: Shiga toxin-producing Escherichia coli; STX 1-2: Shiga toxins 1-2.
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PMID:CFH and CFB mutations in Shiga toxin-associated haemolytic uraemic syndrome in a 6-year-old boy. 3124 18


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