Defective glycosylation of coagulation factor XII underlies hereditary angioedema type III
Identifieur interne : 002F54 ( Main/Exploration ); précédent : 002F53; suivant : 002F55Defective glycosylation of coagulation factor XII underlies hereditary angioedema type III
Auteurs : Jenny Björkqvist [Allemagne, Suède] ; Steven De Maat [Pays-Bas] ; Urs Lewandrowski [Allemagne] ; Antonio Di Gennaro [Suède] ; Chris Oschatz [Suède] ; Kai Schönig [Allemagne] ; Markus M. Nöthen [Allemagne] ; Christian Drouet [France] ; Hal Braley [Australie] ; Marc W. Nolte [Allemagne] ; Albert Sickmann [Allemagne] ; Con Panousis [Australie] ; Coen Maas [Pays-Bas] ; Thomas Renné [Allemagne, Suède]Source :
- The Journal of Clinical Investigation [ 0021-9738 ] ; 2015.
Abstract
Hereditary angioedema type III (HAEIII) is a rare inherited swelling disorder that is associated with point mutations in the gene encoding the plasma protease factor XII (FXII). Here, we demonstrate that HAEIII-associated mutant FXII, derived either from HAEIII patients or recombinantly produced, is defective in mucin-type Thr309-linked glycosylation. Loss of glycosylation led to increased contact-mediated autoactivation of zymogen FXII, resulting in excessive activation of the bradykinin-forming kallikrein-kinin pathway. In contrast, both FXII-driven coagulation and the ability of C1-esterase inhibitor to bind and inhibit activated FXII were not affected by the mutation. Intravital laser-scanning microscopy revealed that, compared with control animals, both
Url:
DOI: 10.1172/JCI77139
PubMed: 26193639
PubMed Central: 4563738
Affiliations:
- Allemagne, Australie, France, Pays-Bas, Suède
- Auvergne-Rhône-Alpes, Bade-Wurtemberg, District d'Arnsberg, District de Cologne, District de Giessen, District de Karlsruhe, Hambourg, Hesse (Land), Rhénanie-du-Nord-Westphalie, Rhône-Alpes, Svealand, Utrecht (province)
- Bonn, Dortmund, Grenoble, Hambourg, Mannheim, Marbourg, Stockholm, Utrecht
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Nöthen</name><affiliation><nlm:aff wicri:cut=" and" id="A7">Institute of Human Genetics</nlm:aff></affiliation><affiliation wicri:level="3"><nlm:aff id="A8">Department of Genomics, Life and Brain Research Center, University of Bonn, Bonn, Germany.</nlm:aff><country xml:lang="fr" wicri:curation="lc">Allemagne</country><wicri:regionArea>Department of Genomics, Life and Brain Research Center, University of Bonn, Bonn</wicri:regionArea><placeName><region type="land" nuts="1">Rhénanie-du-Nord-Westphalie</region><region type="district" nuts="2">District de Cologne</region><settlement type="city">Bonn</settlement></placeName></affiliation></author><author><name sortKey="Drouet, Christian" sort="Drouet, Christian" uniqKey="Drouet C" first="Christian" last="Drouet">Christian Drouet</name><affiliation wicri:level="3"><nlm:aff id="A9">University Joseph Fourier Grenoble, GREPI EA UJF-EFS-CNRS, National Reference Centre for Angioedema, Grenoble, France.</nlm:aff><country xml:lang="fr" wicri:curation="lc">France</country><wicri:regionArea>University Joseph Fourier Grenoble, GREPI EA UJF-EFS-CNRS, National Reference Centre for Angioedema, Grenoble</wicri:regionArea><placeName><region type="region">Auvergne-Rhône-Alpes</region><region type="old region">Rhône-Alpes</region><settlement type="city">Grenoble</settlement></placeName></affiliation></author><author><name sortKey="Braley, Hal" sort="Braley, Hal" uniqKey="Braley H" first="Hal" last="Braley">Hal Braley</name><affiliation wicri:level="1"><nlm:aff id="A10">CSL Ltd., Bio21 Institute, Melbourne, Victoria, Australia.</nlm:aff><country xml:lang="fr" wicri:curation="lc">Australie</country><wicri:regionArea>CSL Ltd., Bio21 Institute, Melbourne, Victoria</wicri:regionArea><wicri:noRegion>Victoria</wicri:noRegion></affiliation></author><author><name sortKey="Nolte, Marc W" sort="Nolte, Marc W" uniqKey="Nolte M" first="Marc W." last="Nolte">Marc W. 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coagulation factor XII underlies hereditary angioedema type III</title><author><name sortKey="Bjorkqvist, Jenny" sort="Bjorkqvist, Jenny" uniqKey="Bjorkqvist J" first="Jenny" last="Björkqvist">Jenny Björkqvist</name><affiliation wicri:level="3"><nlm:aff id="A1">Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.</nlm:aff><country xml:lang="fr" wicri:curation="lc">Allemagne</country><wicri:regionArea>Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center Hamburg-Eppendorf, Hamburg</wicri:regionArea><placeName><settlement type="city">Hambourg</settlement><region type="land" nuts="2">Hambourg</region></placeName></affiliation><affiliation wicri:level="3"><nlm:aff id="A2">Clinical Chemistry Unit, Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.</nlm:aff><country xml:lang="fr" wicri:curation="lc">Suède</country><wicri:regionArea>Clinical Chemistry Unit, Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm</wicri:regionArea><placeName><settlement type="city">Stockholm</settlement><region nuts="2">Svealand</region></placeName></affiliation><affiliation wicri:level="3"><nlm:aff id="A3">Center of Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden.</nlm:aff><country xml:lang="fr" wicri:curation="lc">Suède</country><wicri:regionArea>Center of Molecular Medicine, Karolinska University Hospital, Stockholm</wicri:regionArea><placeName><settlement type="city">Stockholm</settlement><region nuts="2">Svealand</region></placeName></affiliation></author><author><name sortKey="De Maat, Steven" sort="De Maat, Steven" uniqKey="De Maat S" first="Steven" last="De Maat">Steven De Maat</name><affiliation wicri:level="3"><nlm:aff id="A4">Department of Clinical Chemistry and Haematology, University Medical Center Utrecht, Utrecht, Netherlands.</nlm:aff><country xml:lang="fr" wicri:curation="lc">Pays-Bas</country><wicri:regionArea>Department of Clinical Chemistry and Haematology, University Medical Center Utrecht, Utrecht</wicri:regionArea><placeName><settlement type="city">Utrecht</settlement><region nuts="2" type="province">Utrecht (province)</region></placeName></affiliation></author><author><name sortKey="Lewandrowski, Urs" sort="Lewandrowski, Urs" uniqKey="Lewandrowski U" first="Urs" last="Lewandrowski">Urs Lewandrowski</name><affiliation wicri:level="3"><nlm:aff id="A5">Leibniz-Institut für Analytische Wissenschaften – ISAS – e.V., Dortmund, Germany.</nlm:aff><country xml:lang="fr" wicri:curation="lc">Allemagne</country><wicri:regionArea>Leibniz-Institut für Analytische Wissenschaften – ISAS – e.V., Dortmund</wicri:regionArea><placeName><region type="land" nuts="1">Rhénanie-du-Nord-Westphalie</region><region type="district" nuts="2">District d'Arnsberg</region><settlement type="city">Dortmund</settlement></placeName></affiliation></author><author><name sortKey="Di Gennaro, Antonio" sort="Di Gennaro, Antonio" uniqKey="Di Gennaro A" first="Antonio" last="Di Gennaro">Antonio Di Gennaro</name><affiliation wicri:level="3"><nlm:aff id="A2">Clinical Chemistry Unit, Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.</nlm:aff><country xml:lang="fr" wicri:curation="lc">Suède</country><wicri:regionArea>Clinical Chemistry Unit, Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm</wicri:regionArea><placeName><settlement type="city">Stockholm</settlement><region nuts="2">Svealand</region></placeName></affiliation><affiliation wicri:level="3"><nlm:aff id="A3">Center of Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden.</nlm:aff><country xml:lang="fr" wicri:curation="lc">Suède</country><wicri:regionArea>Center of Molecular Medicine, Karolinska University Hospital, Stockholm</wicri:regionArea><placeName><settlement type="city">Stockholm</settlement><region nuts="2">Svealand</region></placeName></affiliation></author><author><name sortKey="Oschatz, Chris" sort="Oschatz, Chris" uniqKey="Oschatz C" first="Chris" last="Oschatz">Chris Oschatz</name><affiliation wicri:level="3"><nlm:aff id="A2">Clinical Chemistry Unit, Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.</nlm:aff><country xml:lang="fr" wicri:curation="lc">Suède</country><wicri:regionArea>Clinical Chemistry Unit, Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm</wicri:regionArea><placeName><settlement type="city">Stockholm</settlement><region nuts="2">Svealand</region></placeName></affiliation><affiliation wicri:level="3"><nlm:aff id="A3">Center of Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden.</nlm:aff><country xml:lang="fr" wicri:curation="lc">Suède</country><wicri:regionArea>Center of Molecular Medicine, Karolinska University Hospital, Stockholm</wicri:regionArea><placeName><settlement type="city">Stockholm</settlement><region nuts="2">Svealand</region></placeName></affiliation></author><author><name sortKey="Schonig, Kai" sort="Schonig, Kai" uniqKey="Schonig K" first="Kai" last="Schönig">Kai Schönig</name><affiliation wicri:level="3"><nlm:aff id="A6">Department of Molecular Biology, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.</nlm:aff><country xml:lang="fr" wicri:curation="lc">Allemagne</country><wicri:regionArea>Department of Molecular Biology, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim</wicri:regionArea><placeName><region type="land" nuts="1">Bade-Wurtemberg</region><region type="district" nuts="2">District de Karlsruhe</region><settlement type="city">Mannheim</settlement></placeName></affiliation></author><author><name sortKey="Nothen, Markus M" sort="Nothen, Markus M" uniqKey="Nothen M" first="Markus M." last="Nöthen">Markus M. Nöthen</name><affiliation><nlm:aff wicri:cut=" and" id="A7">Institute of Human Genetics</nlm:aff></affiliation><affiliation wicri:level="3"><nlm:aff id="A8">Department of Genomics, Life and Brain Research Center, University of Bonn, Bonn, Germany.</nlm:aff><country xml:lang="fr" wicri:curation="lc">Allemagne</country><wicri:regionArea>Department of Genomics, Life and Brain Research Center, University of Bonn, Bonn</wicri:regionArea><placeName><region type="land" nuts="1">Rhénanie-du-Nord-Westphalie</region><region type="district" nuts="2">District de Cologne</region><settlement type="city">Bonn</settlement></placeName></affiliation></author><author><name sortKey="Drouet, Christian" sort="Drouet, Christian" uniqKey="Drouet C" first="Christian" last="Drouet">Christian Drouet</name><affiliation wicri:level="3"><nlm:aff id="A9">University Joseph Fourier Grenoble, GREPI EA UJF-EFS-CNRS, National Reference Centre for Angioedema, Grenoble, France.</nlm:aff><country xml:lang="fr" wicri:curation="lc">France</country><wicri:regionArea>University Joseph Fourier Grenoble, GREPI EA UJF-EFS-CNRS, National Reference Centre for Angioedema, Grenoble</wicri:regionArea><placeName><region type="region">Auvergne-Rhône-Alpes</region><region type="old region">Rhône-Alpes</region><settlement type="city">Grenoble</settlement></placeName></affiliation></author><author><name sortKey="Braley, Hal" sort="Braley, Hal" uniqKey="Braley H" first="Hal" last="Braley">Hal Braley</name><affiliation wicri:level="1"><nlm:aff id="A10">CSL Ltd., Bio21 Institute, Melbourne, Victoria, Australia.</nlm:aff><country xml:lang="fr" wicri:curation="lc">Australie</country><wicri:regionArea>CSL Ltd., Bio21 Institute, Melbourne, Victoria</wicri:regionArea><wicri:noRegion>Victoria</wicri:noRegion></affiliation></author><author><name sortKey="Nolte, Marc W" sort="Nolte, Marc W" uniqKey="Nolte M" first="Marc W." last="Nolte">Marc W. Nolte</name><affiliation wicri:level="3"><nlm:aff id="A11">CSL Behring GmbH, Marburg, Germany.</nlm:aff><country xml:lang="fr" wicri:curation="lc">Allemagne</country><wicri:regionArea>CSL Behring GmbH, Marburg</wicri:regionArea><placeName><region type="land" nuts="1">Hesse (Land)</region><region type="district" nuts="2">District de Giessen</region><settlement type="city">Marbourg</settlement></placeName></affiliation></author><author><name sortKey="Sickmann, Albert" sort="Sickmann, Albert" uniqKey="Sickmann A" first="Albert" last="Sickmann">Albert Sickmann</name><affiliation wicri:level="3"><nlm:aff id="A5">Leibniz-Institut für Analytische Wissenschaften – ISAS – e.V., Dortmund, Germany.</nlm:aff><country xml:lang="fr" wicri:curation="lc">Allemagne</country><wicri:regionArea>Leibniz-Institut für Analytische Wissenschaften – ISAS – e.V., Dortmund</wicri:regionArea><placeName><region type="land" nuts="1">Rhénanie-du-Nord-Westphalie</region><region type="district" nuts="2">District d'Arnsberg</region><settlement type="city">Dortmund</settlement></placeName></affiliation></author><author><name sortKey="Panousis, Con" sort="Panousis, Con" uniqKey="Panousis C" first="Con" last="Panousis">Con Panousis</name><affiliation wicri:level="1"><nlm:aff id="A10">CSL Ltd., Bio21 Institute, Melbourne, Victoria, Australia.</nlm:aff><country xml:lang="fr" wicri:curation="lc">Australie</country><wicri:regionArea>CSL Ltd., Bio21 Institute, Melbourne, Victoria</wicri:regionArea><wicri:noRegion>Victoria</wicri:noRegion></affiliation></author><author><name sortKey="Maas, Coen" sort="Maas, Coen" uniqKey="Maas C" first="Coen" last="Maas">Coen Maas</name><affiliation wicri:level="3"><nlm:aff id="A4">Department of Clinical Chemistry and Haematology, University Medical Center Utrecht, Utrecht, Netherlands.</nlm:aff><country xml:lang="fr" wicri:curation="lc">Pays-Bas</country><wicri:regionArea>Department of Clinical Chemistry and Haematology, University Medical Center Utrecht, Utrecht</wicri:regionArea><placeName><settlement type="city">Utrecht</settlement><region nuts="2" type="province">Utrecht (province)</region></placeName></affiliation></author><author><name sortKey="Renne, Thomas" sort="Renne, Thomas" uniqKey="Renne T" first="Thomas" last="Renné">Thomas Renné</name><affiliation wicri:level="3"><nlm:aff id="A1">Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.</nlm:aff><country xml:lang="fr" wicri:curation="lc">Allemagne</country><wicri:regionArea>Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center Hamburg-Eppendorf, Hamburg</wicri:regionArea><placeName><settlement type="city">Hambourg</settlement><region type="land" nuts="2">Hambourg</region></placeName></affiliation><affiliation wicri:level="3"><nlm:aff id="A2">Clinical Chemistry Unit, Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.</nlm:aff><country xml:lang="fr" wicri:curation="lc">Suède</country><wicri:regionArea>Clinical Chemistry Unit, Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm</wicri:regionArea><placeName><settlement type="city">Stockholm</settlement><region nuts="2">Svealand</region></placeName></affiliation><affiliation wicri:level="3"><nlm:aff id="A3">Center of Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden.</nlm:aff><country xml:lang="fr" wicri:curation="lc">Suède</country><wicri:regionArea>Center of Molecular Medicine, Karolinska University Hospital, Stockholm</wicri:regionArea><placeName><settlement type="city">Stockholm</settlement><region nuts="2">Svealand</region></placeName></affiliation></author></analytic><series><title level="j">The Journal of Clinical Investigation</title><idno type="ISSN">0021-9738</idno><idno type="eISSN">1558-8238</idno><imprint><date when="2015">2015</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>Hereditary angioedema type III (HAEIII) is a rare inherited swelling disorder that is associated with point mutations in the gene encoding the plasma protease factor XII (FXII). Here, we demonstrate that HAEIII-associated mutant FXII, derived either from HAEIII patients or recombinantly produced, is defective in mucin-type Thr309-linked glycosylation. Loss of glycosylation led to increased contact-mediated autoactivation of zymogen FXII, resulting in excessive activation of the bradykinin-forming kallikrein-kinin pathway. In contrast, both FXII-driven coagulation and the ability of C1-esterase inhibitor to bind and inhibit activated FXII were not affected by the mutation. Intravital laser-scanning microscopy revealed that, compared with control animals, both <italic>F12<sup>–/–</sup></italic> mice reconstituted with recombinant mutant forms of FXII and humanized HAEIII mouse models with inducible liver-specific expression of Thr309Lys-mutated FXII exhibited increased contact-driven microvascular leakage. An FXII-neutralizing antibody abolished bradykinin generation in HAEIII patient plasma and blunted edema in HAEIII mice. Together, the results of this study characterize the mechanism of HAEIII and establish FXII inhibition as a potential therapeutic strategy to interfere with excessive vascular leakage in HAEIII and potentially alleviate edema due to other causes.</p></div></front></TEI><affiliations><list><country><li>Allemagne</li><li>Australie</li><li>France</li><li>Pays-Bas</li><li>Suède</li></country><region><li>Auvergne-Rhône-Alpes</li><li>Bade-Wurtemberg</li><li>District d'Arnsberg</li><li>District de Cologne</li><li>District de Giessen</li><li>District de Karlsruhe</li><li>Hambourg</li><li>Hesse (Land)</li><li>Rhénanie-du-Nord-Westphalie</li><li>Rhône-Alpes</li><li>Svealand</li><li>Utrecht (province)</li></region><settlement><li>Bonn</li><li>Dortmund</li><li>Grenoble</li><li>Hambourg</li><li>Mannheim</li><li>Marbourg</li><li>Stockholm</li><li>Utrecht</li></settlement></list><tree><country name="Allemagne"><region name="Hambourg"><name sortKey="Bjorkqvist, Jenny" sort="Bjorkqvist, Jenny" uniqKey="Bjorkqvist J" first="Jenny" last="Björkqvist">Jenny Björkqvist</name></region><name sortKey="Lewandrowski, Urs" sort="Lewandrowski, Urs" uniqKey="Lewandrowski U" first="Urs" last="Lewandrowski">Urs Lewandrowski</name><name sortKey="Nolte, Marc W" sort="Nolte, Marc W" uniqKey="Nolte M" first="Marc W." last="Nolte">Marc W. Nolte</name><name sortKey="Nothen, Markus M" sort="Nothen, Markus M" uniqKey="Nothen M" first="Markus M." last="Nöthen">Markus M. Nöthen</name><name sortKey="Renne, Thomas" sort="Renne, Thomas" uniqKey="Renne T" first="Thomas" last="Renné">Thomas Renné</name><name sortKey="Schonig, Kai" sort="Schonig, Kai" uniqKey="Schonig K" first="Kai" last="Schönig">Kai Schönig</name><name sortKey="Sickmann, Albert" sort="Sickmann, Albert" uniqKey="Sickmann A" first="Albert" last="Sickmann">Albert Sickmann</name></country><country name="Suède"><region name="Svealand"><name sortKey="Bjorkqvist, Jenny" sort="Bjorkqvist, Jenny" uniqKey="Bjorkqvist J" first="Jenny" last="Björkqvist">Jenny Björkqvist</name></region><name sortKey="Bjorkqvist, Jenny" sort="Bjorkqvist, Jenny" uniqKey="Bjorkqvist J" first="Jenny" last="Björkqvist">Jenny Björkqvist</name><name sortKey="Di Gennaro, Antonio" sort="Di Gennaro, Antonio" uniqKey="Di Gennaro A" first="Antonio" last="Di Gennaro">Antonio Di Gennaro</name><name sortKey="Di Gennaro, Antonio" sort="Di Gennaro, Antonio" uniqKey="Di Gennaro A" first="Antonio" last="Di Gennaro">Antonio Di Gennaro</name><name sortKey="Oschatz, Chris" sort="Oschatz, Chris" uniqKey="Oschatz C" first="Chris" last="Oschatz">Chris Oschatz</name><name sortKey="Oschatz, Chris" sort="Oschatz, Chris" uniqKey="Oschatz C" first="Chris" last="Oschatz">Chris Oschatz</name><name sortKey="Renne, Thomas" sort="Renne, Thomas" uniqKey="Renne T" first="Thomas" last="Renné">Thomas Renné</name><name sortKey="Renne, Thomas" sort="Renne, Thomas" uniqKey="Renne T" first="Thomas" last="Renné">Thomas Renné</name></country><country name="Pays-Bas"><region name="Utrecht (province)"><name sortKey="De Maat, Steven" sort="De Maat, Steven" uniqKey="De Maat S" first="Steven" last="De Maat">Steven De Maat</name></region><name sortKey="Maas, Coen" sort="Maas, Coen" uniqKey="Maas C" first="Coen" last="Maas">Coen Maas</name></country><country name="France"><region name="Auvergne-Rhône-Alpes"><name sortKey="Drouet, Christian" sort="Drouet, Christian" uniqKey="Drouet C" first="Christian" last="Drouet">Christian Drouet</name></region></country><country name="Australie"><noRegion><name sortKey="Braley, Hal" sort="Braley, Hal" uniqKey="Braley H" first="Hal" last="Braley">Hal Braley</name></noRegion><name sortKey="Panousis, Con" sort="Panousis, Con" uniqKey="Panousis C" first="Con" last="Panousis">Con Panousis</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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