MOLECULAR-BASES OF COMBINED SUBTOTAL DEFICIENCIES OF C6 AND C7 - THEIR EFFECTS IN COMBINATION WITH OTHER C6 AND C7 DEFICIENCIES

Combined subtotal deficiency of C6 and C7, in which both proteins are expressed at very low levels, has been observed in homozygous form in two families, A defect at the 5' splice donor site of intron 15 of the C6 gene explains the low molecular weight of the C6 protein and is pr obably responsible for its low expressed concentration. The C7 defect is more enigmatic: the protein is of normal molecular weight, low circ ulating concentration, and altered isoelectric point, An Arg > Ser cod on substitution in exon 11 is the only molecular alteration within the mature C7 protein. These defects are associated with a characteristic set of polymorphic DNA markers in the C6/C7 region, forming a distinc t haplotype. The haplotype has been found in combination with a number of other haplotypes containing defective genes that lead either to C6 Or C7 deficiency, but with different consequences, Where it is combin ed with a C6-deficient gene, the serum C7 levels can be surprisingly h igh, possibly because there is no C6 generating <C(56)over bar> to con sume the C7. in contrast, where the C7 genes are both defective (but s till partially functional), there may be a profound deficit of circula ting C7 because there is ample C6 to produce <C(56)over bar> and consu me the already small amount of C7, Each molecular defect has also been found in isolation and has the expected effect.