Center for Reproductive Medicine, Shandong University. National Research Center for Assisted Reproductive Technology and Reproductive Genetics, China, The Key Laboratory of Reproductive Endocrinology (Shandong University), Ministry of Education, Jinan, China.
Advanced Medical Research Institute, Shandong University, Jinan, China.
J Clin Endocrinol Metab. 2020 Oct 1;105(10). doi: 10.1210/clinem/dgaa505.
Premature ovarian insufficiency (POI) is characterized by cessation of menstruation before 40 years of age and elevated serum level of FSH (>25 IU/L). Recent studies have found a few causative genes responsible for POI enriched in meiotic recombination and DNA damage repair pathways.
To investigate the role of variations in homologous recombination genes played in POI pathogenesis.
The whole exome sequencing was performed in 50 POI patients with primary amenorrhea. Functional characterizations of the novel variants were carried out in budding yeast and human cell line.
We identified 8 missense variants in 7 homologous recombination genes, including EXO1, RAD51, RMI1, MSH5, MSH2, MSH6, and MLH1. The mutation p.Thr52Ser in EXO1 impaired the meiotic process of budding yeast and p.Glu68Gly in RAD51-altered protein localization in human cells, both of them impaired the efficiency of homologous recombination repair for DNA double-stranded breaks in human cells.
Our study first linked the variants of EXO1 and RAD51 with POI and further highlighted the role of DNA repair genes in ovarian dysgenesis.
卵巢早衰（POI）的特征是在 40 岁之前闭经和血清 FSH 水平升高（>25IU/L）。最近的研究发现了一些与减数分裂重组和 DNA 损伤修复途径相关的导致 POI 的致病基因。
研究同源重组基因变异在 POI 发病机制中的作用。
对 50 例原发性闭经的 POI 患者进行全外显子组测序。在芽殖酵母和人细胞系中对新变异进行功能特征分析。
我们在 7 个同源重组基因中发现了 8 个错义变异，包括 EXO1、RAD51、RMI1、MSH5、MSH2、MSH6 和 MLH1。EXO1 中的突变 p.Thr52Ser 会损害芽殖酵母的减数分裂过程，RAD51 中的 p.Glu68Gly 会改变蛋白在人细胞中的定位，这两种变异都会降低人细胞中 DNA 双链断裂的同源重组修复效率。
本研究首次将 EXO1 和 RAD51 的变异与 POI 联系起来，并进一步强调了 DNA 修复基因在卵巢发育不良中的作用。
