INHERITED COMPLEMENT C3 DEFICIENCY - A DEFECT IN C3 SECRETION

The molecular basis of inherited complement C3 deficiency in a 20-year -old newly diagnosed male patient was studied. Using an enzyme-linked immunosorbent assay, the patient's C3 serum level was found to be appr oximately 7 mu g/ml, which is less than 1% of normal. In contrast, Nor thern analysis indicated that the patient's C3 mRNA was of normal size and quantity. Peripheral blood monocytes (PBM) and skin fibroblast cu ltures (F) from the patient and from healthy donors were labeled for 2 h with [S-35] methionine. Analysis of cell lysates and supernatants b y immunoprecipitation and sodium dodecyl sulfate-polyacrylamide gel el ectrophoresis (SDS-PAGE) demonstrated normal levels of C3 in lysates o f patient's PBM and E However, C3 secretion in the patient's cells was extremely reduced, with pulse-chase experiments demonstrating a long delay in the disappearance of intracellular C3. Secretion of C1r and f actor B by the patient's cells was normal. Lipopolysaccharide and inte rleukin-1 increased C3 synthesis in the patient's PBM and F, but had n o effect on the secretion. SDS-PAGE analysis of trypsin-cleaved intrac ellular C3 revealed an aberrant cleavage profile for the patient's C3. Collectively, these data indicate that C3 deficiency in this patient is due to a defect in the C3 secretion, probably as the result of abno rmality in the proC3 structure.