Fragile X premutation RNA is sufficient to cause primary ovarian insufficiency in mice
Fragile X premutation RNA is sufficient to cause primary ovarian insufficiency in mice
复制标题
脆性X前突变RNA足以引起小鼠原发性卵巢功能不全
DOI：
10.1093/hmg/dds348
复制
发表时间：
2012-12-01
影响因子：
3.5
通讯作者：
Chen, Dahua
中科院分区：
文献类型：
--
作者：
Lu, Cuiling;Lin, Li;Chen, Dahua
自发性46，XX原发性卵巢功能不全（POI），也称为过早绝经或过早卵巢功能衰竭，是指卵巢功能障碍，导致一系列异常，从不孕到早期绝经为终末期。POI最常见的已知遗传原因是在X连锁脆性X智力低下1（FMR 1）基因的5个非翻译区中CGG重复扩增至55199个拷贝（前突变）。与FMR 1前突变相关的POI被称为脆性X相关POI（FXPOI）。在这里，我们描述了一个携带人类FMR 1前突变等位基因的小鼠模型，并表明FMR 1前突变RNA可以导致卵巢中生长卵泡数量的减少，并足以损害女性生育能力。在该小鼠模型中观察到选择性血清激素水平（包括FSH、LH和17-雌二醇）的变化，其模拟了人类的发现。此外，我们还发现LH诱导的排卵相关基因的表达发生了特异性改变。最后，我们表明FMR 1预突变等位基因可以导致Akt和mTOR蛋白磷酸化减少。这些结果共同表明，FMR 1前突变RNA可能导致与FMR 1前突变携带者相关的POI，Akt/mTOR通路可能作为FXPOI的治疗靶点。
Spontaneous 46,XX primary ovarian insufficiency (POI), also known as opremature menopause' or opremature 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 55199 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 17-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.