FAM171A2基因是前颗粒蛋白表达的关键调控因子，可改变多种神经退行性疾病的风险。

IF 11.7 1区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

Science Advances Pub Date : 2020-10-21 DOI:10.1126/sciadv.abb3063

Wei Xu, Si-Da Han, Can Zhang, Jie-Qiong Li, Yan-Jiang Wang, Chen-Chen Tan, Hong-Qi Li, Qiang Dong, Cui Mei, Lan Tan, Jin-Tai Yu

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引用次数: 7

摘要

前颗粒蛋白(PGRN)是一种分泌性多效糖蛋白，与常见神经退行性疾病的发生有关。了解PGRN的病理生理作用可能有助于揭示生物学基础。我们进行了一项全基因组关联研究，以确定脑脊液(CSF) PGRN水平的遗传调节因子。FAM171A2区常见变异与脑脊液PGRN水平降低相关(rs708384, P = 3.95 × 10-12)。这在另一个独立的队列中得到了重复。rs708384与阿尔茨海默病、帕金森病和额颞叶痴呆的风险增加有关，并可能改变FAM171A2基因的表达。FAM171A2在富含PGRN的血管内皮和小胶质细胞中大量表达。体外研究进一步证实rs708384突变上调FAM171A2的表达，导致PGRN水平下降。总的来说，遗传、分子和生物信息学的发现表明FAM171A2是调节PGRN产生的关键角色。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

The FAM171A2 gene is a key regulator of progranulin expression and modifies the risk of multiple neurodegenerative diseases

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The FAM171A2 gene is a key regulator of progranulin expression and modifies the risk of multiple neurodegenerative diseases

Progranulin (PGRN) is a secreted pleiotropic glycoprotein associated with the development of common neurodegenerative diseases. Understanding the pathophysiological role of PGRN may help uncover biological underpinnings. We performed a genome-wide association study to determine the genetic regulators of cerebrospinal fluid (CSF) PGRN levels. Common variants in region of FAM171A2 were associated with lower CSF PGRN levels (rs708384, P = 3.95 × 10⁻¹²). This was replicated in another independent cohort. The rs708384 was associated with increased risk of Alzheimer’s disease, Parkinson’s disease, and frontotemporal dementia and could modify the expression of the FAM171A2 gene. FAM171A2 was considerably expressed in the vascular endothelium and microglia, which are rich in PGRN. The in vitro study further confirmed that the rs708384 mutation up-regulated the expression of FAM171A2, which caused a decrease in the PGRN level. Collectively, genetic, molecular, and bioinformatic findings suggested that FAM171A2 is a key player in regulating PGRN production.

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来源期刊

Science Advances 综合性期刊-综合性期刊

CiteScore

21.40

自引率

1.50%

发文量

1937

审稿时长

29 weeks

期刊介绍： Science Advances, an open-access journal by AAAS, publishes impactful research in diverse scientific areas. It aims for fair, fast, and expert peer review, providing freely accessible research to readers. Led by distinguished scientists, the journal supports AAAS's mission by extending Science magazine's capacity to identify and promote significant advances. Evolving digital publishing technologies play a crucial role in advancing AAAS's global mission for science communication and benefitting humankind.