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Mutations of C3 in Atypical Hemolytic Uremic Syndrome (aHUS)
Author(s) -
Miller Elizabeth C,
Liszewski M Kathryn,
Gupta Ritu,
Hauhart Richard,
FremeauxBacchi Veronique,
Goodship Timothy,
Atkinson John
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.673.6
Subject(s) - atypical hemolytic uremic syndrome , mutant , mutation , nonsense mutation , complement system , factor h , mutagenesis , compound heterozygosity , alternative complement pathway , genetics , chemistry , gene , microbiology and biotechnology , biology , medicine , antibody , missense mutation
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.