Unique C1 inhibitor dysfunction in a kindred without angioedema. I: A mutant C1 INH that inhibits C1s but not C1r

We have described hereditary incomplete deficiency of the fourth component of complement (C4) in 10 members of a large kindred. C4 deficiency in this kindred is not linked to C4 loci in the HLA region. C4 synthesis is decreased, and C4 catabolism is normal in kindred members with low serum C4 levels. We have discovered a uniquely dysfunctional C1 inhibitor in all C4-deficient members of this kindred. C1 inhibitor dysfunction is revealed by incubating sera of affected members with EDTA, which destroys all C4 activity in these sera, but not in normal sera or sera from individuals with partial C4 deficiencies. The findings show that affected kindred members have a unique mutation in C1 inhibitor. The mutant C1 inhibitor does not prevent the activation of C1s by C1r when serum Ca super(2+) is chelated by EDTA, but its inhibition of C1s is normal in vivo, as shown by normal C2 levels, normal C4 catabolism, and absence of angioedema in C4-deficient members. The nature of the mutation, its selective failure to inhibit C1r, and its relationship to decreased C4 synthesis remain to be defined.