BRCA2 deficiency is a potential driver for human primary ovarian insufficiency
BRCA2 deficiency is a potential driver for human primary ovarian insufficiency
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BRCA2 缺陷是人类原发性卵巢功能不全的潜在驱动因素
DOI：
10.1038/s41419-019-1720-0
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发表时间：
2019-06-17
影响因子：
9
通讯作者：
Xiong, Bo
中科院分区：
文献类型：
--
作者：
Miao, Yilong;Wang, Pan;Xiong, Bo
近几十年来，生殖问题一直是全球妇女健康的首要问题之一。原发性卵巢功能不全（POI）是一种典型的女性疾病，它导致卵泡和卵母细胞的丢失，从而破坏女性的生育能力。然而，由于POI病因的复杂性和人类POI卵母细胞资源的稀缺性，临床上很少有生物标志物被确定，并且没有有效的策略可以应用于治疗POI患者。通过Smart-Seq2和RT2profiler PCR阵列研究DNA损伤与POI之间的可能联系，我们发现同源重组的核心DNA修复基因BRCA 2在两个POI患者卵母细胞中的表达显著降低。基于此，我们建立了Gdf9-Cre基因驱动的卵母细胞特异性基因敲除小鼠模型。Brca2缺陷小鼠由于DNA损伤累积导致卵泡发育停滞和卵母细胞质量缺陷而不育。值得注意的是，在Brca2缺陷的卵母细胞中异位表达Brca2可以部分恢复卵母细胞的成熟和染色体稳定性。总的来说，我们的数据指定明确的缺陷BRCA 2作为卵泡发育和卵母细胞成熟过程中的POI驱动程序，并为BRCA 2缺陷诱导的POI患者提供潜在的生育治疗策略。
Reproductive problem has been one of the top issues for women health worldwide in recent decades. As a typical female disease, primary ovarian insufficiency (POI) results in a loss of ovarian follicles and oocytes that thus destroys women fertility. However, due to the complex of POI etiology and rare resource of human POI oocytes, few biomarkers have been identified in clinics and no effective strategy could be applied to treat POI patients. In the search of possible association between DNA damage and POI by Smart-Seq2 and RT2profiler PCR array, we find thatBRCA2, a core DNA repair gene for homologous recombination shows significantly lower expression in two POI patient oocytes. In line with this, we generated oocyte-specific knockout mouse model driven byGdf9-Cre. TheBrca2-deficient mice are infertile because of the arrested follicle development and defective oocyte quality caused by the accumulation of DNA damage. Notably, ectopic expression of Brca2 inBrca2-deficient oocytes could partially restore the oocyte maturation and chromosome stability. Collectively, our data assign a definite deficiency toBRCA2as a POI driver during follicle development and oocyte maturation, and provide a potential fertility treatment strategy for POI patients induced byBRCA2deficiency.