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- W2295135505 abstract "This non-enteropathic, often familial disease is characterized by a microangiopathic hemolytic anemia, thrombocytopenia and acute renal failure. Dysregulation of the complement system predisposes to this life-threatening thrombomicroangiopathy. Heterozygous mutations in one of three inhibitors (Factor H, MCP, Factor I) that regulate C3 are present in ∼50% of patients. In two large aHUS cohorts, we have now identified mutations in C3 in ∼10% of patients. There were 9 distinct mutations in 14 patients from 11 families. Site directed mutagenesis was performed and the mutant proteins transiently expressed in 293T and COS-1 cells and quantitated by ELISA. One mutant (nonsense) led to a truncated protein and one (Cys to Trp) was not expressed. The expressed mutants were assessed for their binding to regulators and cofactor activity (CA). Five mutants displayed decreased binding (∼30% of WT) to MCP and a corresponding reduction in CA. Four of these also showed a decrease in binding (∼70% of WT) to FH. Thus, we propose that a primary resistance to CA leads to a secondary gain of function. This is the first description of heterozygous, function altering mutations in C3 and their linkage to human disease. They further establish a key role for excessive complement activation predisposing to aHUS and provide insight into binding sites of C3. This work is supported by T32AI007163, R01A1041592, and R01A1037618." @default.
- W2295135505 created "2016-06-24" @default.
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- W2295135505 date "2008-03-01" @default.
- W2295135505 modified "2023-10-17" @default.
- W2295135505 title "Mutations of C3 in Atypical Hemolytic Uremic Syndrome (aHUS)" @default.
- W2295135505 doi "https://doi.org/10.1096/fasebj.22.1_supplement.673.6" @default.
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