PURIFICATION AND CHARACTERIZATION OF 2 FUNCTIONALLY DISTINCT FORMS OF C-1 INHIBITOR FROM A PATIENT WITH ANGIOEDEMA

Abstract

A minority of patients with hereditary angioedema (HAE) have normal concentrations of a dysfunctional C1 [complement component 1] inhibitor protein (C1INH) in their plasmas. C1INH was purified from the plasmas of one such patient before and during treatment with the anabolic steroid stanozolol. The pretreatment plasma and plasma obtained during stanozolol treatment contained varying amounts of 2 extremely similar C1INH proteins that were functionally distinct. The pretreatment plasma contained primarily (94%) dysfunctional C1INH that did not inactivate with purified C.hivin.ls, activated Hageman factor or kallikrein and small amounts (6%) of functionally normal C1INH. Stanozolol treatment increased the plasma concentrations of both proteins and the proportion (23%) of functional C1INH in the plasma. The purified dysfuncitonal and functional C1INH had identical or nearly identical molecular sizes, charges, amino acid compositions and amino sugar contents, and could not be distinguished physicochemically from each other or from normal C1INH. HAE associated with dysfunctional C1INH apparently is due to a defect at the structural locus for 1 C1INH gene; both the dysfunctional C1INH gene and the normal C1INH gene products apparently are present in the plasma of the affected subject. Treatment with stanozolol comparably increased the synthesis of both C1INH proteins. The disproportionate rise in the level of the normal C1INH protein is consistent with the view that it is more rapidly catabolized as a consequence of its interaction with the proteases it inactivates.