AbstractThe 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 approximately 7 μg/ml, which is less than 1 % of normal. In contrast, Northern analysis indicated that the patient's C3 mRNA was of normal size and quantity. Peripheral blood monocytes (PBM) and skin fibroblast cultures (F) from the patient and from healthy donors were labeled for 2 h with [35S] methionine. Analysis of cell lysates and supernatants by immunoprecipitation and sodium dodecyl sulfate‐polyacrylamide gel electrophoresis (SDS‐PAGE) demonstrated normal levels of C3 in lysates of patient's PBM and F. 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 factor B by the patient's cells was normal. Lipopolysaccharide and interleukin‐1 increased C3 synthesis in the patient's PBM and F, but had no effect on the secretion. SDS‐PAGE analysis of trypsin‐cleaved intracellular 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 abnormality in the proC3 structure.