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and Lys380. Met-Lys-bradykinin-Ser-Ser is cleaved from HMWK by the neutrophil proteinase-3 (PR3). The N-terminal cleavage site is between AA p.Leu378 and Met379. It is highly probable that the reported AA change modifies the bradykinin-forming process pointing toward a previously unreported pathomechanism of HAE. We consider that the described KNG1 variant changing the Nterminal cleavage site of bradykinin from HMWK and LMWK could lead to a functionally active but aberrant bradykinin in HAE-KNG1.An aberrant bradykinin could change the process of the inactivation by enzymes such as aminopeptidase 2, angiotensin-converting enzyme, and others, possibly resulting in a prolonged half-life time and thus a higher than normal activity of this mutant bradykinin.Similar to bradykinin, Lys-bradykinin is a high-affinity agonist for the human B2 receptor. It can be cleaved to bradykinin by an arginine aminopeptidase (AAP) in plasma. We cannot rule out that the novel mutation also leads to a modified Lys-bradykinin. Another possibility could be that the mutant HMWK is more easily activated.We are planning to demonstrate the cleaved HMWK products.The results, reported here, strongly support our assumption that the new variant in the KNG1 gene leads to a novel type of HAE, HAE with normal C1-INH and a specific variant in the KNG1 gene or HAE-KNG1.

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