Defective glycosylation of coagulation factor XII underlies hereditary angioedema type III

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 -