Skp2-p27信号通路在卵巢早衰发病中的作用机制研究

Premature ovarian failure (POF) is a complex heritable disease known to be heterogeneous both in etiology and phenotype.The incidence is increased these years and the pathogenic mechanism is still unclear.More than half of these patients are idiopathic POF with unclear etiology. Preliminary study confirmed that PTEN/AKT/FOXO3a signal pathway played an important role in the maintenance of primordial follicles resting and activation which is related to POF. Skp2 and p27 are the downstream genes of this signaling pathway, whether they are associated with human POF is not clear. Gene sequencing and zebra fish models will be used to study the gene mutations and protein function of Skp2 and p27 in 500 cases of idiopathic POF. The result will reveal their role in follicle abnormal activation which is related to the pathogenesis of POF and will provide the basis for the study of pathogenesis of POF genetics.

卵巢早衰（premature ovarian failure，POF）是一种临床高度异质性、病因混杂的疾病，近年来发病呈上升趋势，致病机制尚不清楚，半数以上的患者病因不清属特发性POF。本项目组的前期研究证实：PTEN/AKT/FOXO3a通路在维持始基卵泡静息和启动始基卵泡活化中发挥重要作用，与POF发生密切相关，Skp2、p27是这一信号通路的下游基因，二者是否与人类POF发生相关目前尚不清楚。本项目将借助基因测序分析和斑马鱼模型，拟对500例特发性POF患者进行Skp2、p27基因的突变筛查和蛋白功能研究，探讨其在POF发病机制中的作用，从而阐明卵泡异常激活与POF的相关性，为卵巢早衰遗传学发病机理研究提供依据。

1.我们首次在中国汉族散发卵巢早衰（Premature ovarian failure，POF）患者中对SKP2-P27信号通路的关键基因SKP2和P27进行突变筛查，发现2处已知单核苷酸多态位点（Single nucleotide polymorphisms, SNPs）：rs16908375 (c.165G>A)和rs61755301 (c.846A>G)，SNPs位点发生率与对照人群基因型频率相比没有统计学差异，提示这两处已知SNPs位点不引起SKP2和P27基因功能的改变，SKP2和P27基因突变不是中国汉族POF患者的常见病因。2.完成HELQ基因在192例中国汉族散发POF患者中的突变筛查，发现6处已知SNPs，提示HELQ基因突变不是中国汉族POF患者的常见病因。3.我们在553例中国汉族POF患者与400例月经周期正常女性中探讨既往疾病史、生活习惯等因素与POF发病的相关性。研究结果提示POF可能诱因包括心理压力过大（17.16%）、流产（3.84%）、分娩（2.26%）和过度劳累（0.90%）。盆腔手术史、流行性腮腺炎病史、亲属月经周期异常和化学物质接触史与POF具有显著相关性；偏素饮食、饮茶和饮用矿物质水为卵巢功能的保护性因素等。该研究为卵巢早衰的早期预防提供了依据。