Analysis of dysfunctional C1-inhibitor proteins isolated from individuals with type II hereditary angioedema

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Molecular defects in hereditary angioneurotic edema

Thirty-eight previously unreported, unrelated patients with hereditary angioneurotic edema were studied, and each was found to have a single mutation in the C1 inhibitor gene. On the basis of serine protease inhibitor crystal structure, these and published mutations affect critical domains in the reactive center loop, \u3b1-helices A, B, C, E, and F, and \u3b2-sheets A and C. Almost all mutations, other than in the reactive center loop, occur at residues that are highly conserved among serine protease inhibitors, and the others are likely to interfere with molecular movement. These mutations begin to identify residues critical for molecular function of the C1 inhibitor molecule

A hinge region mutation in C1-inhibitor (Ala436-->Thr) results innonsubstrate-like behavior and in polymerization of the molecule

C1-inhibitor(Mo), a dysfunctional C1-inhibitor molecule produced in two kindred with type II hereditary angioedema, has a mutation at the P10 position (Ala436 to Thr). Like most serpins with hinge region mutations (P14, P12, P10), C1-inhibitor(Mo) loses its inhibitory activity. However, unlike the other hinge region mutations, this mutant is not converted to a substrate. As shown by nondenaturing gel electrophoresis, gel filtration, sucrose density gradient ultracentrifugation, and electron microscopy, C1-inhibitor(Mo) exists in both monomeric and multimeric forms. Polymerization probably results from reactive center loop insertion into the A sheet of an adjacent molecule. Native C1-inhibitor(Mo) was shown to have a thermal stability profile intermediate to those of intact and of cleaved normal C1-inhibitor. Native C1-inhibitor(Mo) did not bind to monoclonal antibody KII, which binds only to reactive center-cleaved normal C1-inhibitor. It did, however, react with monoclonal antibody KOK12, which recognizes complexed or cleaved C1-inhibitor but not intact normal C1-inhibitor. Native C1-inhibitor(Mo), therefore, exists in a conformation similar to the complexed form of normal C1-inhibitor