A synonymous polymorphic variation in ACADM exon 11 affects splicing efficiency and may affect fatty acid oxidation

小基因 RNA剪接 外显子 选择性拼接 生物 单核苷酸多态性 等位基因 遗传学 内含子 基因 基因型 核糖核酸
作者
Georg M. Bruun,Thomas Koed Doktor,Brage S. Andresen
出处
期刊:Molecular Genetics and Metabolism [Elsevier]
卷期号:110 (1-2): 122-128 被引量:22
标识
DOI:10.1016/j.ymgme.2013.06.005
摘要

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.
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