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...
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Frontiers Media S.A.
2023-01-01
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| Series: | Frontiers in Physiology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphys.2022.1090732/full |
| _version_ | 1797961058599567360 |
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| author | Stefan Hintze Stefan Hintze Britta S. Möhl Jessica Beyerl Jessica Beyerl Jessica Beyerl Karin Wulff Andreas Wieser Andreas Wieser Andreas Wieser Andreas Wieser Konrad Bork Peter Meinke |
| author_facet | Stefan Hintze Stefan Hintze Britta S. Möhl Jessica Beyerl Jessica Beyerl Jessica Beyerl Karin Wulff Andreas Wieser Andreas Wieser Andreas Wieser Andreas Wieser Konrad Bork Peter Meinke |
| author_sort | Stefan Hintze |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-11T00:53:26Z |
| format | Article |
| id | doaj.art-8fe081b71e814230a32993612e33fcf2 |
| institution | Directory Open Access Journal |
| issn | 1664-042X |
| language | English |
| last_indexed | 2024-04-11T00:53:26Z |
| publishDate | 2023-01-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Physiology |
| spelling | doaj.art-8fe081b71e814230a32993612e33fcf22023-01-05T07:46:03ZengFrontiers Media S.A.Frontiers in Physiology1664-042X2023-01-011310.3389/fphys.2022.10907321090732Mutant plasminogen in hereditary angioedema is bypassing FXII/kallikrein to generate bradykininStefan Hintze0Stefan Hintze1Britta S. Möhl2Jessica Beyerl3Jessica Beyerl4Jessica Beyerl5Karin Wulff6Andreas Wieser7Andreas Wieser8Andreas Wieser9Andreas Wieser10Konrad Bork11Peter Meinke12Friedrich-Baur-Institute at the Department of Neurology, University Hospital, Ludwig-Maximilians-University Munich, Munich, GermanyFraunhofer Institute for Translational Medicine and Pharmacology ITMP, Immunology, Infection and Pandemic Research, Munich, GermanyInstitute of Virology, School of Medicine, Technical University of Munich/Helmholtz Zentrum München, Munich, GermanyDivision of Infectious Diseases and Tropical Medicine, University Hospital, Ludwig-Maximilians-University Munich, Munich, GermanyMax-von-Pettenkofer Institute, Ludwig-Maximilians-University Munich, Munich, GermanyFraunhofer Institute for Translational Medicine and Pharmacology ITMP, Immunology, Infection and Pandemic Research, Munich, GermanyUniversity Medicine, University of Greifswald, Greifswald, GermanyDivision of Infectious Diseases and Tropical Medicine, University Hospital, Ludwig-Maximilians-University Munich, Munich, GermanyDZIF: German Centre for infection research (DZIF), Partner Site Munich, Munich, GermanyMax-von-Pettenkofer Institute, Ludwig-Maximilians-University Munich, Munich, GermanyFraunhofer Institute for Translational Medicine and Pharmacology ITMP, Immunology, Infection and Pandemic Research, Munich, GermanyDepartment of Dermatology, University Medical Center, Johannes Gutenberg University, Mainz, GermanyFriedrich-Baur-Institute at the Department of Neurology, University Hospital, Ludwig-Maximilians-University Munich, Munich, GermanyHereditary 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.https://www.frontiersin.org/articles/10.3389/fphys.2022.1090732/fullHereditary angioedema (HAE)normal C1-INHHAE-PLGplasminogenFXIIbradykinin |
| spellingShingle | Stefan Hintze Stefan Hintze Britta S. Möhl Jessica Beyerl Jessica Beyerl Jessica Beyerl Karin Wulff Andreas Wieser Andreas Wieser Andreas Wieser Andreas Wieser Konrad Bork Peter Meinke Mutant plasminogen in hereditary angioedema is bypassing FXII/kallikrein to generate bradykinin Frontiers in Physiology Hereditary angioedema (HAE) normal C1-INH HAE-PLG plasminogen FXII bradykinin |
| title | Mutant plasminogen in hereditary angioedema is bypassing FXII/kallikrein to generate bradykinin |
| title_full | Mutant plasminogen in hereditary angioedema is bypassing FXII/kallikrein to generate bradykinin |
| title_fullStr | Mutant plasminogen in hereditary angioedema is bypassing FXII/kallikrein to generate bradykinin |
| title_full_unstemmed | Mutant plasminogen in hereditary angioedema is bypassing FXII/kallikrein to generate bradykinin |
| title_short | Mutant plasminogen in hereditary angioedema is bypassing FXII/kallikrein to generate bradykinin |
| title_sort | mutant plasminogen in hereditary angioedema is bypassing fxii kallikrein to generate bradykinin |
| topic | Hereditary angioedema (HAE) normal C1-INH HAE-PLG plasminogen FXII bradykinin |
| url | https://www.frontiersin.org/articles/10.3389/fphys.2022.1090732/full |
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