Table_1_In-Frame Variants in STAG3 Gene Cause Premature Ovarian Insufficiency.docx

Premature ovarian insufficiency (POI) is a severe clinical syndrome defined by ovarian dysfunction in women less than 40 years old who generally manifest with infertility, menstrual disturbance, elevated gonadotrophins, and low estradiol levels. STAG3 is considered a genetic aetiology of POI, which facilitates entry of REC8 into the nucleus of a cell and plays an essential role in gametogenesis. At present, only six truncated variants associated with POI have been reported; there have been no reports of an in-frame variant of STAG3 causing POI. In this study, two novel homozygous in-frame variants (c.877_885del, p.293_295del; c.891_893dupTGA, p.297_298insAsp) in STAG3 were identified in two sisters with POI from a five-generation consanguineous Han Chinese family. To evaluate the effects of these two variants, we performed fluorescence localization and co-immunoprecipitation analyses using in vitro cell model. The two variants were shown to be pathogenic, as neither STAG3 nor REC8 entered nuclei, and interactions between mutant STAG3 and REC8 or SMC1A were absent. To the best of our knowledge, this is the first report on in-frame variants of STAG3 that cause POI. This finding extends the spectrum of variants in STAG3 and sheds new light on the genetic origins of POI.

早发性卵巢功能不全（Premature ovarian insufficiency, POI）是一种严重的临床综合征，指40岁以下女性出现卵巢功能障碍，通常表现为不孕、月经紊乱、促性腺激素水平升高及雌二醇水平低下。STAG3被认为是POI的遗传病因之一，其可介导REC8进入细胞核，并在配子发生过程中发挥不可或缺的作用。目前仅报道过6种与POI相关的截短变异体，尚未见STAG3框内变异导致POI的相关报道。本研究在一个五代近亲婚配的汉族家系的两名POI患者姐妹中，鉴定出STAG3的两种新型纯合框内变异：c.877_885del（p.293_295del）与c.891_893dupTGA（p.297_298insAsp）。为评估这两种变异的功能影响，我们利用体外细胞模型开展了荧光定位与免疫共沉淀（co-immunoprecipitation）分析。结果显示，这两种变异具有致病性：突变型STAG3与REC8均无法进入细胞核，且突变STAG3与REC8或SMC1A之间不存在相互作用。据我们所知，本研究首次报道了可导致POI的STAG3框内变异。该发现拓展了STAG3的变异谱，为POI的遗传起源研究提供了新的视角。