期刊
MOLECULAR GENETICS AND METABOLISM
卷 110, 期 1-2, 页码 122-128出版社
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.ymgme.2013.06.005
关键词
MCAD; Fatty acid oxidation; Exonic splicing enhancer; mRNA splicing; Serum metabolite concentrations; Functional SNP
资金
- Danish Medical Research Council
- Novo Nordic Foundation
- Aase og Ejnar Danielsens Fond
- Oda og Hans Svenningsens Fond
- Fonden af 1870
- Novo Nordisk Fonden [NNF11OC1015438] Funding Source: researchfish
In recent studies combining genome-wide association and tandem-MS based metabolic profiling, a single-nucleotide polymorphism (SNP), rs211718C > T, located far upstream of the MCAD gene (ACADM) was found to be associated with serum concentrations of medium-chain acylcarnitines indicating improved beta-oxidation of medium-chain fatty acids. We examined the functional basis for this association and identified linkage between rs211718 and the intragenic synonymous polymorphic variant c.1161A > G in ACADM exon 11 (rs1061337). Employing minigene studies we show that the c.1161A allele is associated with exon 11 missplicing, and that the c.1161G allele corrects this missplicing. This may result in production of more full length MCAD protein from the c.1161G allele. Our analysis suggests that the improved splicing of the c.1161G allele is due to changes in the relative binding of splicing regulatory proteins SRSF1 and hnRNP A1. Using publicly available pre-aligned RNA-seq data, we find that the ACADM c.1161G allele is expressed at significantly higher levels than the c.1161A allele across different tissues. This supports that c.1161A > G is a functional SNP, which leads to higher MCAD expression, perhaps due to improved splicing. This study is a proof of principle that synonymous SNPs are not neutral. By changing the binding sites for splicing regulatory proteins they can have significant effects on pre-mRNA splicing and thus protein function. In addition, this study shows that for a sequence variation to have an effect, it might need to change the balance in the relative binding of positive and negative splicing factors. (C) 2013 Elsevier Inc. All rights reserved.
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