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Amelioration of the severity of heparin-binding antithrombin mutations by posttranslational mosaicism

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dc.contributor.authorMartínez-Martínez, Irene
dc.contributor.authorNavarro-Fernández, José
dc.contributor.authorOstergaad, Alice
dc.contributor.authorGutierrez-Gallego, Ricardo
dc.contributor.authorPadilla, José
dc.contributor.authorMiñano, Antonia
dc.contributor.authorPascual, Cristina
dc.contributor.authorMartínez, Constantino
dc.contributor.authorMorena-Barrio, María Eugenia de la
dc.contributor.authorPedersen, Shona
dc.contributor.authorKristensen, Soren Risom
dc.contributor.authorCorral, Javier
dc.contributor.authorBohdan, Nataliya
dc.contributor.authorMorena Barrio, María Eugenia de la
dc.contributor.authorÁguila Martínez, Sonia
dc.contributor.authorVicente García, Vicente
dc.contributor.authorCorral de la Calle, Javier
dc.contributor.departmentMedicina
dc.date.accessioned2024-02-07T13:00:06Z
dc.date.available2024-02-07T13:00:06Z
dc.date.copyright© 2012 by The American Society of Hematology
dc.date.issued2012-04-12
dc.description.abstractThe balance between actions of procoagulant and anticoagulant factors protects organisms from bleeding and thrombosis. Thus, antithrombin deficiency increases the risk of thrombosis, and complete quantitative deficiency results in intrauterine lethality. However, patients homozygous for L99F or R47C antithrombin mutations are viable. These mutations do not modify the folding or secretion of the protein, but abolish the glycosaminoglycan-induced activation of antithrombin by affecting the heparin-binding domain. We speculated that the natural β-glycoform of antithrombin might compensate for the effect of heparin-binding mutations. We purified α- and β-antithrombin glycoforms from plasma of 2 homozygous L99F patients. Heparin affinity chromatography and intrinsic fluorescence kinetic analyses demonstrated that the reduced heparin affinity of the α-L99F glycoform (K(D), 107.9 ± 3nM) was restored in the β-L99F glycoform (K(D), 53.9 ± 5nM) to values close to the activity of α-wild type (K(D), 43.9 ± 0.4nM). Accordingly, the β-L99F glycoform was fully activated by heparin. Similar results were observed for recombinant R47C and P41L, other heparin-binding antithrombin mutants. In conclusion, we identified a new type of mosaicism associated with mutations causing heparin-binding defects in antithrombin. The presence of a fully functional β-glycoform together with the activity retained by these variants helps to explain the viability of homozygous and the milder thrombotic risk of heterozygous patients with these specific antithrombines
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dc.identifier.citationBlood (2012) 120 (4): 900–904
dc.identifier.doihttps://doi.org/10.1182/blood-2012-01-406207
dc.identifier.eissn1528-0020
dc.identifier.issn0006-4971
dc.identifier.urihttp://hdl.handle.net/10201/138906
dc.languageenges
dc.publisherAmerican Society of Hematology
dc.relationThis work was supported by SAF2009-08993 (Ministerio de Ciencia y Tecnologia and Fondo Europeo de Desarrollo Regional [FEDER]), Redes Temáticas de Investigación Cooperativa Red Temática de Investigación Cooperativa en Enfermedades Cardiovasculares RD06/0014/0039 (Instituto de Salud Carlos III and FEDER), Fundación Séneca (04515/GERM/06), and Fundación Mutua Madrileña. es
dc.relation.publisherversionhttps://ashpublications.org/blood/article/120/4/900/105636/Amelioration-of-the-severity-of-heparin-binding
dc.rightsinfo:eu-repo/semantics/openAccesses
dc.rightsAttribution-NonCommercial-NoDerivatives 4.0 Internacional*
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/*
dc.subjectAntithrombinsen
dc.subjectBeta-glycoformen
dc.subjectThrombosisen
dc.subjectHeparin affinityen
dc.subjectAntithrombin iii
dc.subjectMosaicism
dc.subjectMutation
dc.subjectPlasma
dc.titleAmelioration of the severity of heparin-binding antithrombin mutations by posttranslational mosaicismes
dc.typeinfo:eu-repo/semantics/articlees
dc.type.versioninfo:eu-repo/semantics/publishedVersion
dspace.entity.typePublicationes
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relation.isAuthorOfPublication49779dfb-f4b4-4013-9b03-2ad7e3c247b7
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relation.isAuthorOfPublication.latestForDiscovery2bd1c0ae-9811-4ca1-99b7-62b19f79a50b
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