Department of Psychiatry, Washington University School of Medicine, 425 S Euclid Avenue, St Louis, MO 63110, USA.
Department of Neuroscience, Mount Sinai School of Medicine, New York, NY, USA.
Neurobiol Dis. 2020 Jun;139:104817. doi: 10.1016/j.nbd.2020.104817. Epub 2020 Feb 19.
Alzheimer's disease (AD) is a neurodegenerative disease that is clinically characterized by progressive cognitive decline. More than 200 pathogenic mutations have been identified in amyloid-β precursor protein (APP), presenilin 1 (PSEN1) and presenilin 2 (PSEN2). Additionally, common and rare variants occur within APP, PSEN1, and PSEN2 that may be risk factors, protective factors, or benign, non-pathogenic polymorphisms. Yet, to date, no single study has carefully examined the effect of all of the variants of unknown significance reported in APP, PSEN1 and PSEN2 on Aβ isoform levels in vitro. In this study, we analyzed Aβ isoform levels by ELISA in a cell-based system in which each reported pathogenic and risk variant in APP, PSEN1, and PSEN2 was expressed individually. In order to classify variants for which limited family history data is available, we have implemented an algorithm for determining pathogenicity using available information from multiple domains, including genetic, bioinformatic, and in vitro analyses. We identified 90 variants of unknown significance and classified 19 as likely pathogenic mutations. We also propose that five variants are possibly protective. In defining a subset of these variants as pathogenic, individuals from these families may eligible to enroll in observational studies and clinical trials.
阿尔茨海默病（AD）是一种神经退行性疾病，临床上以进行性认知能力下降为特征。在淀粉样蛋白前体蛋白（APP）、早老素 1（PSEN1）和早老素 2（PSEN2）中已鉴定出 200 多种致病突变。此外，APP、PSEN1 和 PSEN2 中也存在常见和罕见的变体，这些变体可能是风险因素、保护因素或良性、非致病性的多态性。然而，迄今为止，没有一项单一的研究仔细研究了 APP、PSEN1 和 PSEN2 中报告的所有意义不明的变体对体外 Aβ 同工型水平的影响。在这项研究中，我们通过 ELISA 分析了 APP、PSEN1 和 PSEN2 中每个报告的致病性和风险变体在基于细胞的系统中的 Aβ 同工型水平。为了对家族史数据有限的变体进行分类，我们实施了一种使用来自多个领域的可用信息（包括遗传、生物信息学和体外分析）确定致病性的算法。我们确定了 90 种意义不明的变体，并将 19 种归类为可能的致病性突变。我们还提出了 5 种可能具有保护作用的变体。在将这些变体中的一部分定义为致病性变体时，来自这些家族的个体可能有资格参加观察性研究和临床试验。
