Mutant plasminogen in hereditary angioedema is bypassing FXII/kallikrein to generate bradykinin

Hereditary angioedema (HAE) is characterized by recurrent localized edema in various organs, which can be potentially fatal. There are different types of hereditary angioedema, which include genetic deficiency of C1 inhibitor (C1-INH) and hereditary angioedema with normal C1-INH (HAEnCI). In HAEnCI patients mutations have been identified in the , , , , , and genes. The release of bradykinin from kininogen the kallikrein-kinin system (KKS) has been shown to be the main mediator in HAE-FXII, but for HAE-PLG there are only first indications how the mutations can result in bradykinin release. Here we identified in a multi-generation HAE-PLG family an additional mutation, resulting in the loss of one allele. There were no differences in the clinical presentation between HAE-PLG patients with and without the additional mutation, thus we concluded that the kallikrein-kinin system is bypassed in HAE-PLG. Structural modeling and assays using purified proteins confirmed the mutation c.988A>G; p.K330E to be a gain of function mutation resulting in an increased bradykinin release by direct cleavage of high molecular weight kininogen (HMWK). Thus, we can provide clinical and experimental evidence that mutant plasminogen in HAE-PLG is bypassing FXII/kallikrein to generate bradykinin.