原发性卵巢功能不全（POI）以 40 岁前卵巢功能障碍为特征，导致高促性腺激素性性腺功能减退症，伴有严重低雌激素血症和血清促性腺激素升高。POI 表现广泛，从卵巢发育不全和原发性闭经到青春期后继发性闭经 [1]。最近的一项 meta 分析估计其全球患病率为 3.5% [2]。POI 病因高度异质，遗传缺陷显著占不明原因病例的 60% 以上 [3], [4]。在遗传原因中，骨形态发生蛋白 15（BMP15）基因已在几种动物模型中进行了广泛研究，包括实验模型和自然发生突变 [5], [6], [7]，强调了其在调节不同哺乳动物物种生育力方面保守且关键的作用 [8], [9], [10], [11]。此外，BMP15 基因变异与人类 POI 发展之间的关联已得到确立 [12], [13], [14]。
BMP15 基因位于 X 染色体（Xp11.22）上，编码属于 TGF-beta 超家族的生长和分化因子。它主要由卵母细胞表达，但其 mRNA 也已在卵丘细胞中检测到 [15], [16]。BMP15 特异性作用于体细胞卵巢颗粒细胞（GCs），调节增殖和分化 [17]。
体外 studies using isolated GCs and cumulus-oocyte complexes have demonstrated that BMP15 promotes early follicular growth by stimulating Kit Ligand expression, thereby exhibiting mitotic activity [18]. Recent studies in immortalized non-luteinized human GCs, showed that BMP15 can further enhance follicular growth and ovulation by inducing FSHR expression [19]. In antral follicles of bovine and porcine species, BMP15 exhibits a dose-dependent protective role against cumulus cell apoptosis by regulating the expression of both pro-survival and pro-apoptotic genes [20], [21]. Additionally, BMP15 knockdown significantly affects both porcine GCs and oocytes development, including suppression of cell proliferation and differentiation [11]. In mouse early stage preantral follicles, Bmp15 activates Bmpr1b and leads to increased expression of Id transcription factors and Smad6/7, which is associated with inhibiting growth and promoting follicular degeneration. However, when GDF9 factor is present, BMP15's effect changes: instead of promoting atresia, it significantly enhances follicle growth [10]. These findings collectively indicate that the effects of BMP15 on follicular development are intricately regulated, exhibit stage-specificity, and show functional differences between species [22], highlighting the complexity of its role in regulating ovarian follicle development.
尽管 BMP15 在人类卵巢卵泡发生中发挥基础旁分泌作用，但BMP15 基因内已知的遗传改变只能解释少数 POI 病例，患病率在 1.5 到 12% 之间变化 [23], [24], [25]，取决于考虑的人群和使用研究标准。POI 的高遗传异质性进一步限制了对其遗传景观的解读，这导致下一代测序（NGS）经常识别意义不明确的变异，使得候选基因优先级排序具有挑战性。同时，BMP15 信号在人类 GCs 中的下游效应因子在很大程度上仍未被表征。为了解决这些局限性，我们假设 GCs 中 BMP15 诱导基因内的遗传扰动可能有助于 POI 发病机理。为验证这一假设，我们首先通过对 BMP15 刺激的人 GCs 进行微阵列基因表达分析来寻找这些基因，然后通过对 POI 女性进行目标外显子组测序分析所得的差异表达基因（DEGs）。
