Dysregulation of the
complement alternative pathway is involved in the pathogenesis of several diseases, including the
kidney diseases atypical hemolytic uremic syndrome (aHUS) and C3 glomerulopathy (C3G). In a patient, initially diagnosed with chronic
glomerulonephritis, possibly C3G, and who 6 years later had an episode of aHUS, a heterozygous missense mutation leading to a
tryptophan to
arginine exchange (W198R) in the
factor H (FH)
complement control
protein (CCP) 3 domain has previously been identified. The aim of this study was to clarify the functional relevance of this mutation. To this end, wild-type (FH1-4WT) and mutant (FH1-4W198R) CCPs 1-4 of FH were expressed as
recombinant proteins. The FH1-4W198R mutant showed decreased C3b binding compared with FH1-4WT. FH1-4W198R had reduced cofactor and decay accelerating activity compared with the wild-type
protein.
Hemolysis assays demonstrated impaired capacity of FH1-4W198R to protect rabbit erythrocytes from human
complement-mediated lysis, and also to prevent lysis of sheep erythrocytes in human serum induced by a
monoclonal antibody binding in FH CCP5 domain, compared with that of FH1-4WT. Thus, the FH W198R exchange results in impaired
complement alternative pathway regulation. The heterozygous nature of this mutation in the index patient may explain the manifestation of two diseases, likely due to different triggers leading to
complement dysregulation in plasma or on cell surfaces.