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Defective glycosylation of coagulation factor XII underlies hereditary angioedema type III
Jenny Björkqvist, … , Coen Maas, Thomas Renné
Jenny Björkqvist, … , Coen Maas, Thomas Renné
Published July 20, 2015
Citation Information: J Clin Invest. 2015;125(8):3132-3146. https://doi.org/10.1172/JCI77139.
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Research Article Vascular biology

Defective glycosylation of coagulation factor XII underlies hereditary angioedema type III

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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

Jenny Björkqvist, Steven de Maat, Urs Lewandrowski, Antonio Di Gennaro, Chris Oschatz, Kai Schönig, Markus M. Nöthen, Christian Drouet, Hal Braley, Marc W. Nolte, Albert Sickmann, Con Panousis, Coen Maas, Thomas Renné

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Figure 1

HAEIII patients express a FXII protein that lacks glycosylation at Thr309.

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HAEIII patients express a FXII protein that lacks glycosylation at Thr30...
(A) Clinical presentation of an acute swelling attack in a female HAEIII patient. (B) Pedigree of a French HAEIII family carrying the autosomal dominant inherited Thr309Lys FXII mutation. Squares and circles denote men and women, respectively. Black symbols represent individuals with mutation, and white symbols indicate healthy family members who do not harbor the FXII_Thr309Lys mutation. (C) FXII in HAEIII patient plasma samples migrates as a doublet. Plasma from HAEIII patients is indicated by 1–4 and 6–8 (B) and 9–12, indicating 4 HAEIII patients from unrelated families from France, Spain, and Germany. Plasma from a healthy individual (5 indicated in B), pooled normal plasma (NP), individual normal plasma (IP), and FXII-deficient plasma (FXII-def) are shown. A representative photographic film of n = 3 is shown. (D) Fragment mass spectrum of peptide Leu292-Arg311 being glycosylated with a HexHexNAcNeuAc glycan. A b-ion series is partially identified from b2 to b9, and several y-ions (*) corresponding to the peptide moiety, having lost the carbohydrate part, are shown. N-acetylneuraminic acid (NeuAc) is readily lost under tandem-MS conditions, and consecutive loss of hexoses and N-acetylhexosamines is observed within the y-ion series. FXII mutation Thr309Lys in the proline-rich region is indicated in the peptide sequence.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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