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首页 » 华人研究 » HMG:陈大华研究组建立了人类卵巢早衰疾病相关的FMR1前突变体小鼠疾病模型

HMG:陈大华研究组建立了人类卵巢早衰疾病相关的FMR1前突变体小鼠疾病模型

来源:中国科学院动物研究所 2012-08-27 22:25

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。

8月21日Huamn Molecular Genetics在线发表了动物研究所陈大华实验室和Emory大学金鹏实验室合作的最新研究成果。他们以携带人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。最后他们揭示了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。这是第一个人类在该疾病上的小鼠遗传学模型。(生物谷Bioon.com)

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

Cuiling Lu, Li Lin, Huiping Tan, Hao Wu, Stephanie L. Sherman, Fei Gao, Peng Jin and Dahua Chen

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 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.

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