In-Frame Variants in STAG3 Gene Cause Premature Ovarian Insufficiency
In-Frame Variants in STAG3 Gene Cause Premature Ovarian Insufficiency
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STAG3 基因的框内变异导致卵巢早衰
DOI：
10.3389/fgene.2019.01016
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发表时间：
2019-11-14
影响因子：
3.7
通讯作者：
Du, Juan
中科院分区：
文献类型：
--
作者：
Xiao, Wen-Juan;He, Wen-Bin;Du, Juan
卵巢功能不全（POI）是一种严重的临床综合征，以40岁以下女性卵巢功能障碍为定义，通常表现为不孕、月经紊乱、促性腺激素升高和雌二醇水平低。STAG3被认为是POI的遗传病因，它促进REC8进入细胞核，在配子发生中起重要作用。目前，仅报道了6个与POI相关的截断变异；没有帧内STAG3变异引起POI的报道。本研究在一个汉族5代近亲家族中发现了两个新的同框内纯合变异（c.877_885del, p.293_295del; c.891_893dupTGA, p.297_298insAsp）。为了评估这两种变体的影响，我们使用体外细胞模型进行了荧光定位和共免疫沉淀分析。由于STAG3和REC8均未进入细胞核，并且突变体STAG3与REC8或SMC1A之间不存在相互作用，这两种变异体被证明具有致病性。据我们所知，这是第一个关于帧内STAG3变异导致POI的报告。这一发现扩大了STAG3变异的范围，并为POI的遗传起源提供了新的线索。
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.