Center for Reproductive Medicine, Shandong University, Jinan, China.
Key Laboratory of Reproductive Endocrinology of Ministry of Education, Shandong University, Jinan, China.
J Clin Endocrinol Metab. 2022 Aug 18;107(9):2589-2597. doi: 10.1210/clinem/dgac368.
Premature ovarian insufficiency (POI) affects 1% to 3.7% of women at reproductive age, and its etiology is heterogeneous. The linker of nucleoskeleton and cytoskeleton (LINC) complex, consisting of KASH5 and SUN1, plays an indispensable role in meiotic homolog pairing, determining the ovarian reserve. However, their roles in the pathogenesis of POI are unknown.
To investigate the role of KASH5 variation in the pathogenesis of POI.
Whole-exome sequencing was performed in a pedigree with 2 POI patients. The pathogenicity of identified variant was illustrated by in vitro functional studies, and its effect on ovarian function and meiosis was confirmed by histological analysis and oocyte spreads with Kash5 C-terminal deleted mice model.
A homozygous splicing site variant in KASH5 (c.747G > A) was identified. In vitro studies found the variant disturbed the nuclear membrane localization of KASH5 and its binding with SUN1. Moreover, the Kash5 C-terminal deleted mice revealed defective meiotic homolog pairing and accelerated depletion of oocytes.
The splicing site variant in KASH5 is responsible for POI due to defective meiotic homolog pairing and accelerated depletion of oocytes. Our study is the first to report disorganized LINC complex participating in POI pathogenesis, potentially suggesting the essential roles of meiotic telomere attachment and dynein-driven proteins for chromosome movement in ovarian function maintenance.
卵巢早衰（POI）影响 1%至 3.7%的育龄妇女，其病因具有异质性。核骨架和细胞骨架（LINC）连接体复合物由 KASH5 和 SUN1 组成，在减数分裂同源体配对中发挥不可或缺的作用，决定卵巢储备。然而，它们在 POI 发病机制中的作用尚不清楚。
研究 KASH5 变异在 POI 发病机制中的作用。
对 2 名 POI 患者的家系进行全外显子组测序。通过体外功能研究阐明鉴定出的变异的致病性，并通过 KASH5 C 端缺失小鼠模型的组织学分析和卵母细胞展开来证实其对卵巢功能和减数分裂的影响。
发现 KASH5 中的一个纯合剪接位点变异（c.747G>A）。体外研究发现该变异干扰了 KASH5 的核膜定位及其与 SUN1 的结合。此外，Kash5 C 端缺失小鼠表现出减数分裂同源体配对缺陷和卵母细胞加速耗竭。
KASH5 中的剪接位点变异导致 POI，原因是减数分裂同源体配对缺陷和卵母细胞加速耗竭。我们的研究首次报道了紊乱的 LINC 复合物参与 POI 发病机制，可能表明减数分裂端粒附着和动力蛋白驱动蛋白在维持卵巢功能中的染色体运动的重要作用。
