Vasquez Jared B, Simpson James F, Harpole Ryan, Estus Steven
Department of Physiology and Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, USA.
J Alzheimers Dis. 2017;59(2):633-641. doi: 10.3233/JAD-170872.
Both common and rare polymorphisms within ABCA7 have been associated with Alzheimer's disease (AD). In particular, the rare AD associated polymorphism rs200538373 was associated with altered ABCA7 exon 41 splicing and an AD risk odds ratio of ∼1.9. To probe the role of this polymorphism in ABCA7 splicing, we used minigene studies and qPCR of human brain RNA. We report aberrant ABCA7 exon 41 splicing in the brain of a carrier of the rs200538373 minor C allele. Moreover, minigene studies show that rs200538373 acts as a robust functional variant in vitro. Lastly, although the ABCA7 isoform with an extended exon 41 is predicted to undergo nonsense mediated RNA decay, this was not supported by qPCR analyses, which showed relatively normal ABCA7 mRNA levels in the carrier of the rs200538373 minor C allele. In summary, rs200538373 is a functional polymorphism that alters ABCA7 exon 41 splicing without grossly altering the level of ABCA7 mRNA.
ABCA7基因内的常见和罕见多态性均与阿尔茨海默病（AD）相关。特别是，罕见的与AD相关的多态性rs200538373与ABCA7第41外显子剪接改变以及约1.9的AD风险比值比相关。为了探究这种多态性在ABCA7剪接中的作用，我们使用了小基因研究和人脑RNA的qPCR。我们报告了rs200538373次要C等位基因携带者大脑中ABCA7第41外显子的异常剪接。此外，小基因研究表明rs200538373在体外是一个强大的功能变体。最后，虽然预测具有延长第41外显子的ABCA7异构体将经历无义介导的RNA降解，但qPCR分析并不支持这一点，qPCR分析显示rs200538373次要C等位基因携带者中ABCA7 mRNA水平相对正常。总之，rs200538373是一种功能性多态性，可改变ABCA7第41外显子剪接而不会显著改变ABCA7 mRNA水平。
