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Hintze, S.* ; Möhl, B.S. ; Beyerl, J.* ; Wulff, K.* ; Wieser, A.* ; Bork, K.* ; Meinke, P.*

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

Front. Physiol. 13:1090732 (2023)
DOI PMC
Creative Commons Lizenzvertrag
Open Access Gold möglich sobald Verlagsversion bei der ZB eingereicht worden ist.
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 F12, PLG, KNG1, ANGPT1, MYOF, and HS3ST6 genes. The release of bradykinin from kininogen via 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 PLG mutations can result in bradykinin release. Here we identified in a multi-generation HAE-PLG family an additional F12 mutation, resulting in the loss of one F12 allele. There were no differences in the clinical presentation between HAE-PLG patients with and without the additional F12 mutation, thus we concluded that the kallikrein-kinin system is bypassed in HAE-PLG. Structural modeling and in vitro assays using purified proteins confirmed the PLG 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.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
Schlagwörter Fxii ; Hae-plg ; Hereditary Angioedema (hae) ; Bradykinin ; Kallikrein-kinin System (kks) ; Normal C1-inh ; Plasminogen; Molecular-weight Kininogen; Plasma Kallikrein; Mechanism; Mutation
ISSN (print) / ISBN 1664-042X
e-ISSN 1664-042X
Zeitschrift Frontiers in Physiology
Quellenangaben Band: 13, Heft: , Seiten: , Artikelnummer: 1090732 Supplement: ,
Verlag Frontiers
Verlagsort Lausanne
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Virology (VIRO)
Förderungen Deutsche Forschungsgemeinschaft (DFG, German Research foundation)