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Título:	Role of six single nucleotide polymorphisms, risk factors in coronary disease, in OLR1 alternative splicing
Autor/a:	Tejedor Vaquero, Juan Ramón, 1984-; Tilgner, Hagen, 1980-; Iannone, Camilla, 1984-; Guigó Serra, Roderic; Valcárcel, J. (Juan)
Abstract:	The OLR1 gene encodes the oxidized low-density lipoprotein receptor (LOX-1), which is responsible for the cellular uptake of oxidized LDL (Ox-LDL), foam cell formation in atheroma plaques and atherosclerotic plaque rupture. Alternative splicing (AS) of OLR1 exon 5 generates two protein isoforms with antagonistic functions in Ox-LDL uptake. Previous work identified six single nucleotide polymorphisms (SNPs) in linkage disequilibrium that influence the inclusion levels of OLR1 exon 5 and correlate with the risk of cardiovascular disease. Here we use minigenes to recapitulate the effects of two allelic series (Low- and High-Risk) on OLR1 AS and identify one SNP in intron 4 (rs3736234) as the main contributor to the differences in exon 5 inclusion, while the other SNPs in the allelic series attenuate the drastic effects of this key SNP. Bioinformatic, proteomic, mutational and functional high-throughput analyses allowed us to define regulatory sequence motifs and identify SR protein family members (SRSF1, SRSF2) and HMGA1 as factors involved in the regulation of OLR1 AS. Our results suggest that antagonism between SRSF1 and SRSF2/HMGA1, and differential recognition of their regulatory motifs depending on the identity of the rs3736234 polymorphism, influence OLR1 exon 5 inclusion and the efficiency of Ox-LDL uptake, with potential implications for atherosclerosis and coronary disease.
Materia(s):	-Alternative splicing -Malalties coronàries -Empalmament (Genètica) -OLR1 -Alternative splicing -SNP -SR proteins -RRM -Linkage disequilibrium -Coronary disease
Derechos:	© 2015 Tejedor et al. This article is distributed exclusively by the RNA Society for the first 12 months after the full-issue publication date (see http://rnajournal.cshlp.org/site/misc/terms.xhtml). After 12 months, it is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/bync/4.0/. http://creativecommons.org/licenses/by-nc/4.0
Tipo de documento:	Artículo Artículo - Versión publicada
Editor:	Cambridge University Press
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