A mechanism for hereditary angioedema caused by a lysine 311-to-glutamic acid substitution in plasminogen

Patients with hereditary angioedema (HAE) experience episodes of bradykinin (BK)-induced swelling of skin and mucosal membranes. The most common cause is reduced plasma activity of C1 inhibitor, the main regulator of the proteases plasma kallikrein (PKa) and factor XIIa (FXIIa). Recently, patients with HAE were described with a Lys(311) to glutamic acid substitution in plasminogen (Plg), the zymogen of the protease plasmin (Plm). Adding tissue plasminogen activator to plasma containing Plg-Glu(311) vs plasma containing wild-type Plg (Plg-Lys(311)) results in greater BK generation. Similar results were obtained in plasma lacking prekallikrein or FXII (the zymogens of PKa and FXIIa) and in normal plasma treated with a PKa inhibitor, indicating Plg-Glu(311) induces BK generation independently of PKa and FXIIa. Plm-Glu(311) cleaves high and low molecular weight kininogens (HK and LK, respectively), releasing BK more efficiently than Plm-Lys(311). Based on the plasma concentrations of HK and LK, the latter may be the source of most of the BK generated by Plm-Glu(311). The lysine analog epsilon-aminocaproic acid blocks Plm-catalyzed BK generation. The Glu(311) substitution introduces a lysine-binding site into the Plg kringle 3 domain, perhaps altering binding to kininogens. Plg residue 311 is glutamic acid in most mammals. Glu(311) in patients with HAE, therefore, represents reversion to the ancestral condition. Substantial BK generation occurs during Plm-Glu(311) cleavage of human HK, but not mouse HK. Furthermore, mouse Plm, which has Glu(311), did not liberate BK from human kininogens more rapidly than human Plg-Lys(311). This indicates Glu(311) is pathogenic in the context of human Plm when human kininogens are the substrates.

Automated summary

Patients with hereditary angioedema (HAE) experience episodes of bradykinin-induced swelling. A substitution of Lys(311) with glutamic acid in plasminogen (Plg) leads to increased bradykinin generation, indicating the pathogenic role of Glu(311) in HAE. The Glu(311) substitution introduces a lysine-binding site in the Plg kringle 3 domain, possibly altering the binding to kininogens.