Defective glycosylation of coagulation factor XII underlies hereditary angioedema type III
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Defective glycosylation of coagulation factor XII underlies hereditary angioedema type III. / Björkqvist, Jenny; de Maat, Steven; Lewandrowski, Urs; Di Gennaro, Antonio; Oschatz, Chris; Schönig, Kai; Nöthen, Markus M; Drouet, Christian; Braley, Hal; Nolte, Marc W; Sickmann, Albert; Panousis, Con; Maas, Coen; Renné, Thomas.
in: J CLIN INVEST, Jahrgang 125, Nr. 8, 03.08.2015, S. 3132-46.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Defective glycosylation of coagulation factor XII underlies hereditary angioedema type III
AU - Björkqvist, Jenny
AU - de Maat, Steven
AU - Lewandrowski, Urs
AU - Di Gennaro, Antonio
AU - Oschatz, Chris
AU - Schönig, Kai
AU - Nöthen, Markus M
AU - Drouet, Christian
AU - Braley, Hal
AU - Nolte, Marc W
AU - Sickmann, Albert
AU - Panousis, Con
AU - Maas, Coen
AU - Renné, Thomas
PY - 2015/8/3
Y1 - 2015/8/3
N2 - 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 F12-/- 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.
AB - 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 F12-/- 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.
KW - Adult
KW - Amino Acid Substitution
KW - Animals
KW - Antibodies, Neutralizing
KW - Blood Coagulation
KW - Bradykinin
KW - Disease Models, Animal
KW - Factor XII
KW - Female
KW - Glycosylation
KW - Hereditary Angioedema Type III
KW - Humans
KW - Mice
KW - Mice, Knockout
KW - Mutation, Missense
U2 - 10.1172/JCI77139
DO - 10.1172/JCI77139
M3 - SCORING: Journal article
C2 - 26193639
VL - 125
SP - 3132
EP - 3146
JO - J CLIN INVEST
JF - J CLIN INVEST
SN - 0021-9738
IS - 8
ER -