生物通报道：来自中科院动物研究所，美国埃默里大学的研究人员发表了题为“Fragile X Premutation RNA is Sufficient to Cause Primary Ovarian Insufficiency in Mice”的文章，建立了原发性卵巢功能不全第一个小鼠遗传学模型，相关成果公布在Huamn Molecular Genetics杂志上。

这项研究由中科院动物研究所陈大华实验室和美国埃默里大学金鹏实验室合作完成。

原发性卵巢功能不全（POI），也称作卵巢早衰（POF），是卵巢功能衰竭导致提前闭经的现象。临床调查表明，小于40岁的POF发生率为1%，小于30岁的POF发生率为0.1%。遗传学上研究发现，脆性X染色体综合症，即X染色体长臂FMR1基因外显子1的5’非翻译区有55-199的CGG重复序列，是导致POI的主要病因之一，被称为FXPOI。然而，FMR1前突变序列是如何影响卵巢功能进而导致POI的分子机制还不是很清楚；FMR1 CGG重复是改变了FMRP的表达水平，还是共同导致FXPOI仍然有待揭示。

在这篇文章中，研究人员以携带人FMR1前突变序列的转基因小鼠为研究对象，发现该小鼠卵巢中生长卵泡的数量减少，而原始卵泡的数量不变；血清中促性腺激素FSH和LH以及17β雌二醇水平发生改变，这与人类疾病具有相同的表型。同时，LH诱导的排卵相关基因的表达水平也特异性地发生改变。最后，研究人员揭示了FMR1前突变序列能够导致磷酸化Akt及mTOR的下调。

这些研究结果表明FMR1前突变序列能够引起POI，Akt/mTOR信号通路可能成为FXPOI的治疗靶。这是人类在该疾病上的第一个小鼠遗传学模型。

（生物通：万纹）

原文摘要：

Fragile X Premutation RNA is Sufficient to Cause Primary Ovarian Insufficiency in Mice

Spontaneous 46,XX primary ovarian insufficiency (POI), also known as “premature menopause” or “premature ovarian failure” (POF), 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 to 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 of selective serum hormone levels, including FSH, LH, and 17ß-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.

打赏

下载安捷伦电子书《通过细胞代谢揭示新的药物靶点》探索如何通过代谢分析促进您的药物发现研究

10x Genomics新品Visium HD 开启单细胞分辨率的全转录组空间分析！

欢迎下载Twist《不断变化的CRISPR筛选格局》电子书

单细胞测序入门大讲堂 - 深入了解从第一个单细胞实验设计到数据质控与可视化解析

下载《细胞内蛋白质互作分析方法电子书》