The synthesis and secretion of factor H, a regulatory protein of the complement system, were studied in skin fibroblasts from an H-deficient child who has chronic hypocomplementemic renal disease. In normal fibroblasts, factor H transcripts of 4.3 and 1.8 kilobase pairs (kb) encode a 155-kDa protein containing short consensus repeat (SCR) domains 1-20 and a 45-kDa protein which contains SCRs 1-7, respectively. The patient's fibroblasts expressed normal amounts of the 4.3- and 1.8-kb messages constitutively and after tumor necrosis factor-α/interferon-γ stimulation. Lysates of [35S]methionine-labeled fibroblasts from the patient contained the 155- and 45-kDa H polypeptides, but secretion of the 155-kDa protein was blocked; the 45-kDa protein was secreted with normal kinetics. The patient's plasma lacked the 155-kDa protein but contained the small form of H. Moreover, in fibroblasts the retained 155-kDa factor H protein was not degraded, even after 12 h. Immunoflourescent staining and confocal microscopic imaging of the patient's fibroblasts indicated that factor H was retained in the endoplasmic reticulum. Sequence analysis of reverse transcription-polymerase chain reaction products (the entire coding region) and genomic DNA revealed a T1679C substitution on one allele and a G2949A substitution on the other (C518R mutation in SCR 9 and C991Y mutation in SCR 16, respectively). Both mutations affect conserved cysteine residues characteristic of SCR modules and therefore predict profound changes in the higher order structure of the 155-kDa factor H protein. These data provide the first description of a molecular mechanism for factor H deficiency and yield important insights into the normal secretory pathway for this and other plasma proteins with SCR motifs.