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Título: | Amelioration of the severity of heparin-binding antithrombin mutations by posttranslational mosaicism |
Fecha de publicación: | 2012 |
Editorial: | American Society of Hematology |
Cita bibliográfica: | Blood (2012) 120 (4): 900–904 |
ISSN: | Print: 0006-4971 Electronic: 1528-0020 |
Palabras clave: | Anithrombin Beta-glycoform Thrombosis Heparin affinity |
Resumen: | The 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 antithrombin |
Autor/es principal/es: | Martínez-Martínez, Irene Navarro-Fernández, José Ostergaad, Alice Gutierrez-Gallego, Ricardo Padilla, José Miñano, Antonia Pascual, Cristina Martínez, Constantino Morena-Barrio, María Eugenia de la Águila, Sonia Pedersen, Shona Kristensen, Soren Vicente, Vicente Corral, Javier |
Facultad/Departamentos/Servicios: | Facultades, Departamentos, Servicios y Escuelas::Departamentos de la UMU::Medicina |
URI: | http://hdl.handle.net/10201/138906 |
DOI: | https://doi.org/10.1182/blood-2012-01-406207 |
Tipo de documento: | info:eu-repo/semantics/article |
Número páginas / Extensión: | 6 |
Derechos: | info:eu-repo/semantics/openAccess Attribution-NonCommercial-NoDerivatives 4.0 Internacional |
Descripción: | ©<2012>. This manuscript version is made available under the CC-BY-NC 4.0 license http://creativecommons.org/licenses/by-nc-nd/4.0/ This document is the, Published, version of a Published Work that appeared in final form in Blood. To access the final edited and published work see: https://doi.org/10.1182/blood-2012-01-406207 |
Aparece en las colecciones: | Artículos: Medicina |
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