Publication: Identification of Antithrombin-Modulating Genes. Role
of LARGE, a Gene Encoding a Bifunctional
Glycosyltransferase, in the Secretion of Proteins?
Authors
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
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Publisher
Public Library of Science
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DOI
https://doi.org/10.1371/journal.pone.0064998
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info:eu-repo/semantics/article
Description
©<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
Abstract
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.
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Citation
Plos One, 2013; 8(5): e64998.
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