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Compound heterozygosity involving Antithrombin Cambridge II (p.Ala416Ser) in antithrombin deficiency.

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dc.contributor.authorÁguila Martínez, Sonia
dc.contributor.authorMartínez-Martínez, Irene
dc.contributor.authorCollado, Miriam
dc.contributor.authorLlamas, Pilar
dc.contributor.authorAntón, Ana I.
dc.contributor.authorMartínez-Redondo, Consuelo
dc.contributor.authorPadilla, José
dc.contributor.authorMiñano, Antonia
dc.contributor.authorMorena Barrio, María Eugenia de la
dc.contributor.authorGarcía-Avello, Ángel
dc.contributor.authorVicente García, Vicente
dc.contributor.authorCorral de la Calle, Javier
dc.contributor.departmentMedicina Interna
dc.date.accessioned2026-02-16T10:09:15Z
dc.date.available2026-02-16T10:09:15Z
dc.date.copyright© 2014 International Society on Thrombosis and Haemostasis
dc.date.issued2013-03-10
dc.description.abstractBackground: The characterization of natural mutants identified in patients with antithrombin deficiency has helped to identify functional domains or regions of this key anticoagulant and the mechanisms involved in the deficiency, as well as to define the clinical prognosis. Recently, we described an abnormal glycosylation in a pleiotropic mutant (K241E) that explained the impaired heparin affinity and the mild risk of thrombosis in carriers. Objectives: To evaluate the effects of different natural pleiotropic mutations on the glycosylation of antithrombin and their functional effects. Methods: Five pleiotropic mutations identified in patients with antithrombin deficiency and located at each one of the strands of the C-sheet were selected (K241E, M251I, M315K, F402L, and P429L). Recombinant mutants were generated and purified. Glycoform heterogeneity and conformational sensitivity were studied with electrophoresis, proteomic analysis, and glycomic analysis. Heparin affinity was evaluated from intrinsic fluorescence. Reactivity assays with factor Xa, thrombin and neutrophil elastase in the presence or absence of heparin were also performed. Results and Conclusions: Pleiotropic mutants, except for that with the M315K mutation, which affects a non-exposed residue, showed two glycoforms. Variant 1, with abnormal glycosylation, had reduced heparin affinity and severely affected reactivity with the target proteases. In contrast, variant 2, with similar electrophoretic mobility and heparin affinity to wild-type antithrombin, had impaired inhibitory activity that was partially compensated for by activation with heparin. Our results suggest the C-sheet of antithrombin as a new region that is relevant for proper maturation of the N-glycans. Therefore, pleiotropic mutations lead to glycosylation defects that are responsible for the reduced heparin affinity
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dc.format.extent10
dc.identifier.citationJournal of Thrombosis and Haemostasis, 12: 1131–1140
dc.identifier.doi10.1160/TH12-09-0707
dc.identifier.eissn1538-7836
dc.identifier.issn1538-7933
dc.identifier.urihttp://hdl.handle.net/10201/205344
dc.languageeng
dc.publisherElsevier
dc.relationThis study was supported by grants 04515 ⁄GERM⁄ 06 (Fundación Seneca), PI12/00657 (ISCIII & FEDER), RD06⁄0014⁄0039 (ISCIII & FEDER), SA holds a FPI grant from Ministerio de Ciencia y Tecnología. IM-M is a researcher from “Fundación para la Formación e Investigación Sanitarias de la Región de Murcia”. ME de la M-B is a holder of a predoctoral research grant from ISCIII
dc.relation.publisherversionhttps://onlinelibrary.wiley.com/doi/10.1111/jth.12606
dc.rights.accessRightsinfo:eu-repo/semantics/restrictedAccess
dc.subjectAntithrombin III
dc.subjectAntithrombin III deficiency
dc.subjectGlycosylation
dc.subjectIsolation & purification
dc.subjectRecombinant proteins
dc.subject.odsObjetivo 3: Salud
dc.titleCompound heterozygosity involving Antithrombin Cambridge II (p.Ala416Ser) in antithrombin deficiency.
dc.typeinfo:eu-repo/semantics/article
dc.type.versioninfo:eu-repo/semantics/publishedVersion
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