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dc.contributor.authorMartínez-Martínez, Irenees_ES
dc.contributor.authorOrdóñez, Adrianaes_ES
dc.contributor.authorNavarro-Fernández, Josées_ES
dc.contributor.authorPérez-Lara, Ángeles_ES
dc.contributor.authorGutiérrez-Gallego, Ricardoes_ES
dc.contributor.authorGiraldo, R.es_ES
dc.contributor.authorMartínez, Constantinoes_ES
dc.contributor.authorLlop, Estheres_ES
dc.contributor.authorVicente, Vicentees_ES
dc.contributor.authorCorral, Javieres_ES
dc.identifier.citationHaematologica 95(8):1358-1365 (2010)es_ES
dc.description8 p.-8 fig.es_ES
dc.description.abstractBackground Identification of mutations in the SERPINC1 gene has revealed different mechanisms responsible for antithrombin deficiency. Deletions and nonsense mutations associate with type I deficiency. Certain missense mutations cause type II deficiency by affecting the heparin binding site or the reactive center loop, while others result in type I deficiency by intracellular retention or RNA instability. Design and Methods We studied the molecular, biochemical, proteomic and glycomic characterization of a new natural mutant (K241E) that may be classified as pleiotropic. Results The mutation caused a significant decrease in the anticoagulant activity mainly due to a reduced heparin affinity and a modification of the electrostatic potential that might explain the impaired ability of the mutant protein to form complexes with the target protease in the absence of heparin. Mass spectrometry and glycomic analyses confirmed an increased molecular weight of 800 Da in the mutant protein possibly due to core-fucosylation, provoking the loss of heparin affinity. Additionally, carriers of this mutation also have a minor mutant isoform that still followed normal glycosylation, retaining similar heparin affinity to wild-type α−antithrombin, and certain anticoagulant activity, which may explain the milder thrombotic risk of patients carrying this mutation. Similar results were observed using recombinant K241E antithrombin molecules. Conclusions Our data suggest a new mechanism involved in antithrombin type II deficiency by indirectly affecting the glycosylation of a natural variant. Additional studies are required to confirm this hypothesis.es_ES
dc.description.sponsorshipthis work was partially supported by 04515/GERM/06 from Fundación Séneca, SAF2006-06212 and SAF2009-08993 (MICINN & FEDER), RETICS(RECAVA RD06/0014/0039) from ISCIII, Fundación Mutua Madrileña, and BFU2006-00494 (MCyT).es_ES
dc.publisherFerrata Storti Foundationes_ES
dc.relation.isversionofPublisher's versiones_ES
dc.titleAntithrombin Murcia (K241E) causing antithrombin deficiency: a possible role for altered glycosylationes_ES
dc.description.peerreviewedPeer reviewedes_ES
dc.relation.publisherversionhttp://dx.doi.org/ 10.3324/haematol.2009.015487es_ES
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