MOLECULAR-BASIS OF A NEW-TYPE OF C1Q-DEFICIENCY ASSOCIATED WITH A NONFUNCTIONAL LOW-MOLECULAR-WEIGHT (LMW) C1Q - PARALLELS AND DIFFERENCES TO OTHER KNOWN GENETIC C1Q-DEFECTS

Analysis of an abnormal Clq molecule of individuals of a Moroccan fami ly by ultracentrifugation in sucrose gradients revealed a low molecula r weight Clq (LMW-C1q). We investigated the molecular basis of this de fect by sequencing all six exons of the three Clq genes. One point mut ation in the codon for Gly at position 15 (GGT) of the B chain was fou nd resulting in an amino acid substitution to Asp (GAT). The exchange not only leads to an interruption of the collagen-like motif Gly-X-Y, but also introduces one negatively charged residue per B chain which r esults in two additional charges per structural subunit (A-B, C-C, A-B ). The mutation which has been identified by DNA-sequencing in the Clq -deficient younger brother of the propositus was confirmed by PCR-EcoR V-RFLP in the sister and the propositus himself. This mutation is very similar to a mutation previously described in another case of functio nal Clq deficiency where Gly at position 6 of the C chain was substitu ted by a large positively charged residue (Arg). Again, a LMW-C1q was demonstrated. These point mutations that lead to amino acid substituti ons result in the production of a LMW-C1q where the formation of funct ionally active 11S C1q consisting of three structural subunits appears to be inhibited by the introduction of six additional charges, one pe r B or C chain, respectively, in the collagenous region of the molecul e. (C) 1997 Elsevier Science B.V.