title: Defective glycosylation of coagulation factor XII underlies hereditary angioedema type III.
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 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.
authors.forename: Jenny
authors.initials: J
authors.lastname: Björkqvist
authors.forename: Steven
authors.initials: S
authors.lastname: de Maat
authors.forename: Urs
authors.initials: U
authors.lastname: Lewandrowski
authors.forename: Antonio
authors.initials: A
authors.lastname: Di Gennaro
authors.forename: Chris
authors.initials: C
authors.lastname: Oschatz
authors.forename: Kai
authors.initials: K
authors.lastname: Schönig
authors.forename: Markus M
authors.initials: MM
authors.lastname: Nöthen
authors.forename: Christian
authors.initials: C
authors.lastname: Drouet
authors.forename: Hal
authors.initials: H
authors.lastname: Braley
authors.forename: Marc W
authors.initials: MW
authors.lastname: Nolte
authors.forename: Albert
authors.initials: A
authors.lastname: Sickmann
authors.forename: Con
authors.initials: C
authors.lastname: Panousis
authors.forename: Coen
authors.initials: C
authors.lastname: Maas
authors.forename: Thomas
authors.initials: T
authors.lastname: Renné
mesh_terms: D000328:Adult; D019943:Amino Acid Substitution; D000818:Animals; D057134:Antibodies, Neutralizing / Q000494:pharmacology; D001777:Blood Coagulation; D001920:Bradykinin / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D005174:Factor XII / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006031:Glycosylation / Q000187:drug effects; D056828:Hereditary Angioedema Type III / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D020125:Mutation, Missense
chemical_list: D057134:Antibodies, Neutralizing; D005174:Factor XII; D001920:Bradykinin