State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, PR China.
Hum Mol Genet. 2012 Dec 1;21(23):5039-47. doi: 10.1093/hmg/dds348. Epub 2012 Aug 21.
Spontaneous 46,XX primary ovarian insufficiency (POI), also known as 'premature menopause' or 'premature ovarian failure', refers to ovarian dysfunction that results in a range of abnormalities, from infertility to early menopause as the end stage. The most common known genetic cause of POI is the expansion of a CGG repeat to 55-199 copies (premutation) in the 5' untranslated region in the X-linked fragile X mental retardation 1 (FMR1) gene. POI associated with the FMR1 premutation is referred to as fragile X-associated POI (FXPOI). Here, we characterize a mouse model carrying the human FMR1 premutation allele and show that FMR1 premutation RNA can cause a reduction in the number of growing follicles in ovaries and is sufficient to impair female fertility. Alterations in selective serum hormone levels, including FSH, LH and 17β-estradiol, are seen in this mouse model, which mimics findings in humans. In addition, we also find that LH-induced ovulation-related gene expression is specifically altered. Finally, we show that the FMR1 premutation allele can lead to reduced phosphorylation of Akt and mTOR proteins. These results together suggest that FMR1 premutation RNA could cause the POI associated with FMR1 premutation carriers, and the Akt/mTOR pathway may serve as a therapeutic target for FXPOI.
自发性 46,XX 原发性卵巢功能不全（POI），也称为“过早绝经”或“卵巢早衰”，是指卵巢功能障碍导致一系列异常，从不孕到早绝经。POI 的最常见已知遗传原因是脆性 X 智力低下 1 基因（FMR1）5'非翻译区的 CGG 重复扩增至 55-199 个拷贝（前突变）。与 FMR1 前突变相关的 POI 称为脆性 X 相关 POI（FXPOI）。在这里，我们描述了一种携带人类 FMR1 前突变等位基因的小鼠模型，并表明 FMR1 前突变 RNA 可导致卵巢中生长卵泡数量减少，并足以损害女性生育能力。该小鼠模型中存在选择性血清激素水平的改变，包括 FSH、LH 和 17β-雌二醇，与人类的发现相似。此外，我们还发现 LH 诱导的排卵相关基因表达也发生了特异性改变。最后，我们表明 FMR1 前突变等位基因可导致 Akt 和 mTOR 蛋白磷酸化减少。这些结果表明，FMR1 前突变 RNA 可能导致与 FMR1 前突变携带者相关的 POI，Akt/mTOR 通路可能是 FXPOI 的治疗靶点。
