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Título: | Identification of Antithrombin-Modulating Genes. Role of LARGE, a Gene Encoding a Bifunctional Glycosyltransferase, in the Secretion of Proteins? |
Fecha de publicación: | 2013 |
Editorial: | Public Library of Science |
Cita bibliográfica: | Plos One, 2013; 8(5): e64998. |
ISSN: | Electronic: 1932-6203 |
Palabras clave: | Antithrombin Large Glycosylation Modulating genes |
Resumen: | The haemostatic relevance of antithrombin together with the low genetic variability of SERPINC1, and the high heritability of plasma levels encourage the search for modulating genes. We used a hypothesis-free approach to identify these genes, evaluating associations between plasma antithrombin and 307,984 polymorphisms in the GAIT study (352 individuals from 21 Spanish families). Despite no SNP reaching the genome wide significance threshold, we verified milder positive associations in 307 blood donors from a different cohort. This validation study suggested LARGE, a gene encoding a protein with xylosyltransferase and glucuronyltransferase activities that forms heparin-like linear polysaccharides, as a potential modulator of antithrombin based on the significant association of one SNPs, rs762057, with anti-FXa activity, particularly after adjustment for age, sex and SERPINC1 rs2227589 genotype, all factors influencing antithrombin levels (p = 0.02). Additional results sustained this association. LARGE silencing inHepG2 and HEK-EBNA cells did not affect SERPINC1 mRNA levels but significantly reduced the secretion of antithrombin with moderate intracellular retention. Milder effects were observed on a1-antitrypsin, prothrombin and transferrin. Our study suggests LARGE as the first known modifier of plasma antithrombin, and proposes a new role for LARGE in modulating extracellular secretion of certain glycoproteins. |
Autor/es principal/es: | Morena-Barrio, María Eugenia de la Buil, Alfonso Antón, Ana Isabel Martínez-Martínez, Irene Miñano, Antonia Guriérrez-Gallego, Ricardo Navarro-Fernandez, José Águila, Sonia Souto, Juan Carlos Vicente, Vicente Soria, José Manuel Corral, Javier |
URI: | http://hdl.handle.net/10201/138893 |
DOI: | https://doi.org/10.1371/journal.pone.0064998 |
Tipo de documento: | info:eu-repo/semantics/article |
Número páginas / Extensión: | 8 |
Derechos: | info:eu-repo/semantics/openAccess Attribution-NonCommercial-NoDerivatives 4.0 Internacional |
Descripción: | ©<2013>. 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 Plos One. To access the final edited and published work see: https://doi.org/10.1371/journal.pone.0064998 |
Aparece en las colecciones: | Artículos: Medicina |
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