Non-sense and missense mutations in the structural genes of complement component C1q A and C chains are linked with two different types of complete selective C1q deficiencies.

To shed light on the molecular basis of two different types of complete C1q deficiency, we performed extensive Southern blot analysis and sequenced all exons of the genes coding for the A, B, and C chains of C1q on two groups of deficient patients. In one family with three cases of complete C1q deficiency we found a point mutation in the codon for glutamine (CAG) at position 186 of the A chain that led to a termination codon (TAG). No gene products of any of the three genes were found in the patients' sera, indicating that full length polypeptides of the A, B, and C chains are required to form and secrete functional C1q. A second point mutation was found in a patient with a complete functional C1q defect. The abnormal C1q molecule had been shown to have a low m.w. of approximately 150,000 and a sedimentation coefficient of below 7S. The mutation occurred in the codon for glycine in position 6 of the C chain where a single base exchange (G-->A transition) has led to an arginine residue. In the parents and son of patient G we could demonstrate the heterozygous state of the mutation by the occurrence of both bases in question, G and A. The interruption of the collagen-like triplet motif Gly-X-Y and, even more likely, the introduction of a large positively charged side chain at the N-terminus of the polypeptide may inhibit the assembly of three structural subunits consisting of two A-B dimers and one C-C dimer to form the 11S C1q macromolecule.