DNA同源重组基因EXO1和BRCA2在早发性卵巢功能不全发病中的作用和致病机制研究

早发性卵巢功能不全（Premature ovarian insufficiency，POI）是指女性40岁之前出现卵巢功能减退，发病率约为1%-5%，是女性不孕症的主要病因之一。随着社会发展和女性生育年龄推迟，POI发病率呈逐年上升趋势，不仅影响女性身心健康，也成为影响社会人口增速和结构的重要因素。为拓展对POI遗传学病因的认识，我们对50例原发性POI患者进行了全外显子组测序，并首次发现同源重组基因EXO1和BRCA2的高致病风险突变。前期研究发现EXO1突变能够影响酵母减数分裂和体细胞的同源重组修复；最新构建的BRCA2点突变小鼠在出生后卵母细胞迅速丢失，该模型与既往报道的差异提示基因组水平的BRCA2缺陷将导致更早阶段的生殖细胞发育异常。本项目拟借助携带人源突变的小鼠模型，进一步研究EXO1和BRCA2突变在卵母细胞减数分裂和卵泡发育中的作用，探讨其导致POI发生的具体机制。

Premature ovarian insufficiency (POI) is characterized by cessation of menstruation occurs before the age of 40 years. Approximately 1%-5% of women are affected by POI, which is one of the causes of female infertility. With the social changes and postponed childbearing plan of women, the incidence of POI is increasing year by year, which not only affects the physical and mental health of women, but also becomes an important factor affecting the growth rate and structure of the population. To expand the understanding of the genetic etiology of POI, we performed whole exome sequencing in 50 patients with primary POI, and identified mutations in homologous gene EXO1 and BRCA2. Our studies showed that the EXO1 mutation disturbed meiosis of yeast and homologous recombination efficiency of human cell line. The point mutant mouse model demonstrated progressive loss of oocytes, which was different from previous report, indicating genomic BRCA2 defects might affect germ cell development at earlier stage. In the project, we attempt to illustrate the influence of EXO1 and BRCA2 on oogenesis and follicle development using the point mutant mouse, furthermore, explore the role of homologous recombination pathway played in pathogenesis of POI.