Nonsense-codon-mediated decay in human hereditary complement C3 deficiency.

C3 occupies a central position in the complement pathway, mediating such diverse functions as convertase activity, opsonization and anaphylotoxin production. The deficiency of this protein is a rare autosomal recessive inherited disease, characterized by severe recurrent infections and immune complex disorders. We looked for molecular alterations that could explain the C3 deficiency present in a Brazilian boy of consanguineous parents who suffered from recurrent bacterial infections. Using reverse-transcriptase polymerase chain reaction to amplify C3 mRNA from LPS-stimulated fibroblasts from the patient, we demonstrated that his C3 gene has no large structural aberrations. However, after sequencing the amplified and cloned products we found: (1). a L314P amino acid substitution; (2). silent mutations at codons P577, S798 and A1437; and finally, (3). an R848STer substitution that results in the production of a truncated protein. Densitometry studies revealed a lower C3 mRNA concentration in the patient's fibroblasts, suggesting an inherent instability of his C3 mRNA. Our results indicate the presence of a premature termination codon in the C3 gene that results in a lack of the protein in patient's serum, which correlates with the acceleration of C3 mRNA decay in the patient's fibroblasts. This mRNA instability is consistent with a nonsense-codon-mediated decay process that ensures the elimination of possible deleterious truncated proteins, which, in the case of constitutively expressed abundant proteins such as C3, may otherwise accumulate to significant levels, leading to toxicity.