原發(fā)性卵巢功能不全（POI）,，也稱作卵巢早衰（POF）,，是卵巢功能衰竭導(dǎo)致提前閉經(jīng)的現(xiàn)象。臨床調(diào)查表明小于40歲的POF發(fā)生率為1%,，小于30歲的POF發(fā)生率為0.1%,。遺傳學(xué)上研究發(fā)現(xiàn)脆性X染色體綜合癥，即X染色體長臂FMR1基因外顯子1的5’非翻譯區(qū)有55-199的CGG重復(fù)序列,，是導(dǎo)致POI的主要病因之一,，被稱為FXPOI。然而FMR1前突變序列是如何影響卵巢功能進(jìn)而導(dǎo)致POI的分子機(jī)制還不是很清楚,，F(xiàn)MR1 CGG重復(fù)是改變了FMRP的表達(dá)水平還是共同導(dǎo)致FXPOI仍然有待揭示,。
8月21日Huamn Molecular Genetics在線發(fā)表了動物研究所陳大華實驗室和Emory大學(xué)金鵬實驗室合作的最新研究成果。他們以攜帶人FMR1前突變序列的轉(zhuǎn)基因小鼠為研究對象,，發(fā)現(xiàn)該小鼠卵巢中生長卵泡的數(shù)量減少,，而原始卵泡的數(shù)量不變。血清中促性腺激素FSH和LH以及17β雌二醇水平發(fā)生改變,，這與人類疾病具有相同的表型,。同時，LH誘導(dǎo)的排卵相關(guān)基因的表達(dá)水平也特異性地發(fā)生改變,。最后他們揭示了FMR1前突變序列能夠?qū)е铝姿峄疉kt及mTOR的下調(diào),。這些研究結(jié)果表明FMR1前突變序列能夠引起POI，Akt/mTOR信號通路可能成為FXPOI的治療靶。這是第一個人類在該疾病上的小鼠遺傳學(xué)模型,。（生物谷Bioon.com）
doi: 10.1093/hmg/dds348
PMC:
PMID:
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.
