斜坡序列可能解释了配对免疫球蛋白样2型受体α（）中同义变异与阿尔茨海默病的关联。
Ramp sequence may explain synonymous variant association with Alzheimer's disease in the Paired Immunoglobulin-like Type 2 Receptor Alpha ().
作者信息
Miller Justin B, Brandon J Anthony, McKinnon Lauren M, Sabra Hady W, Lucido Chloe C, Gonzalez Murcia Josue D, Nations Kayla A, Payne Samuel H, Ebbert Mark T W, Kauwe John S K, Ridge Perry G
机构信息
Department of Pathology and Laboratory Medicine, University of Kentucky, Lexington, KY 40506, USA.
Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY 40506, USA.
出版信息
bioRxiv. 2025 Jan 8:2025.01.06.631528. doi: 10.1101/2025.01.06.631528.
BACKGROUND
Synonymous variant () in the Paired Immunoglobulin-like Type 2 Receptor Alpha () gene was previously associated with decreased risk for Alzheimer's disease (AD) in genome-wide association studies, but its biological impact is largely unknown.
OBJECTIVE
We hypothesized that decreases mRNA and protein levels by destroying a ramp of slowly translated codons at the 5' end of .
METHODS
We assessed predicted effects on through quantitative polymerase chain reactions (qPCR) and enzyme-linked immunosorbent assays (ELISA) using Chinese hamster ovary (CHO) cells.
RESULTS
Both mRNA (=1.9184 × 10) and protein (=0.01296) levels significantly decreased in the mutant versus the wildtype in the direction that we predicted based on destroying a ramp sequence.
CONCLUSIONS
We show that alone directly impacts mRNA and protein expression, and ramp sequences may play a role in regulating AD-associated genes without modifying the protein product.
背景
在全基因组关联研究中，配对免疫球蛋白样2型受体α（PIR-A）基因中的同义变异（rs75932628）先前与阿尔茨海默病（AD）风险降低相关，但其生物学影响在很大程度上尚不清楚。
目的
我们推测rs75932628通过破坏PIR-A 5'端缓慢翻译密码子的一段序列来降低mRNA和蛋白质水平。
方法
我们使用中国仓鼠卵巢（CHO）细胞，通过定量聚合酶链反应（qPCR）和酶联免疫吸附测定（ELISA）评估rs75932628对PIR-A的预测影响。
结果
基于破坏一段序列的预测方向，与野生型相比，突变体中的mRNA（P = 1.9184 × 10⁻⁶）和蛋白质（P = 0.01296）水平均显著降低。
结论
我们表明，rs75932628单独直接影响PIR-A mRNA和蛋白质表达，并且该段序列可能在不改变蛋白质产物的情况下在调节AD相关基因中发挥作用。
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