原發(fā)性卵巢功能不全（POI）是指卵巢濾泡的耗竭，導(dǎo)致40歲前不孕。這種情況的特征是月經(jīng)停止（閉經(jīng)或少經(jīng)）至少4個月，促性腺激素水平增加（FSHLH），雌激素水平降低。 1942年，奧爾布賴特
一、原發(fā)性卵巢早衰導(dǎo)讀
根據(jù)《人的基因序列變化與人體疾病表征》，原發(fā)性卵巢功能不全簡稱為POI，是指卵巢濾泡的耗竭，導(dǎo)致40歲前不孕。這種情況的特征是月經(jīng)停止（閉經(jīng)或少經(jīng)）至少4個月，促性腺激素水平增加（FSH>LH），雌激素水平降低。
1942年，奧爾布賴特和他的同事報告了先進例原發(fā)性卵巢功能不全。佳學(xué)基因發(fā)現(xiàn)，對于這種疾病的描術(shù)，使用了不同的名稱。在國際上也是如此。歐洲人類生殖和胚胎學(xué)學(xué)會的指南推薦在研究和臨床中使用“卵巢早衰”來描述這種疾病。而美國婦產(chǎn)科學(xué)會（ACOG）委員會則支持“原發(fā)性卵巢功能不全”。美國國立衛(wèi)生研究院堅持認(rèn)為這一術(shù)語是恰當(dāng)?shù)?，因為有些POI患者可能會出現(xiàn)自發(fā)性妊娠；因此，POI可以與自然更年期區(qū)分開來，這個術(shù)語可以用來描述卵巢功能不全伴閉經(jīng)表現(xiàn)。一些作者選擇了“卵巢發(fā)育不全”一詞來形容POI，但是如果解剖學(xué)上沒有出現(xiàn)異常，使用這一詞語則明顯不當(dāng)。
佳學(xué)基因根據(jù)不同的使用場景，選擇使用不同的表述方法，目的是為了更好的傳遞知識。本文采用原發(fā)性卵巢功能不全來描述這一疾病。
二、原發(fā)性卵巢早衰的疾病表征和患病率
POI患者表現(xiàn)出廣泛的臨床表型，該病可以在青春期至40歲的女性中發(fā)生?；颊呖杀憩F(xiàn)為原發(fā)性閉經(jīng)，這種情況通常在年輕時診斷為青春期延遲、無乳房發(fā)育和月經(jīng)初潮，而繼發(fā)性閉經(jīng)的診斷年齡在20至40歲之間，其特征是青春期發(fā)育正常，月經(jīng)周期不規(guī)則閉經(jīng)。繼發(fā)性閉經(jīng)是賊常見的POI表型。
POI的廣泛臨床表現(xiàn)已在不同的人群中得到證實。通過對675名女性原發(fā)性卵巢早衰進行的研究表明，繼發(fā)性閉經(jīng)發(fā)生率為84%，高于原發(fā)性閉經(jīng)（16%）。青春期延遲的特點是患者表現(xiàn)為原發(fā)性閉經(jīng)以及乳房發(fā)育不全或不有效（70%），這是由于在這么小的年齡段雌激素水平低所致。相比之下，在另一對74名卵巢早衰所做的研究中，評估了51名原發(fā)性閉經(jīng)和23名繼發(fā)性閉經(jīng)。原發(fā)性閉經(jīng)的高患病率可能是由于表型嚴(yán)重，因為原發(fā)性閉經(jīng)主要在內(nèi)分泌科進行評估，而表現(xiàn)為繼發(fā)性閉經(jīng)的輕度表型則傾向于由婦科來處理。
雖然POI的發(fā)生情況與種族有關(guān)，但缺乏流行病學(xué)數(shù)據(jù)。然而，患病率似乎隨著年齡增長而增加（20歲時為1:10000，30歲為1:1000，40歲為1:100）。
在另一行研究中發(fā)現(xiàn)，在普通人群中，POI的患病率（1.9%）高于先前所證明的。在1036918名女性中，1.7%表現(xiàn)為自發(fā)性POI，其中的0.2%的被診斷為醫(yī)源性POI。此外，在美國的7個地點對40-55歲的婦女進行了橫斷面調(diào)查（全國婦女研究[SWAN]），確定了11652名婦女中自我報告的POI患病率，沒有明顯的種族區(qū)別。事實上，有1.1%的女性患有POI，其中1.0%是白人，1.4%是非裔美國人，1.4%是西班牙裔，0.5%是中國人，0.1%是日本人。在巴西，POI的患病率仍不清楚。
三、診斷
根據(jù)目前的美國和歐洲指南，POI診斷是通過連續(xù)兩次測量促性腺激素水平，兩次之間的間隔至少1個月（絕經(jīng)期范圍內(nèi)FSH水平升高通常大于20 IU/ml）和閉經(jīng)至少3或4個月。
POI診斷確認(rèn)后，應(yīng)進行染色體分析、脆性X染色體突變（FMR1）分析、腎上腺（21羥化酶）和甲狀腺抗體評估，以及盆腔超聲檢查[1]。這種篩查可能有助于確定POI的病因；然而，已經(jīng)確定大多數(shù)POI病例仍然沒有明確的病因，這可能是由于大多數(shù)遺傳病因分析是采用基因檢測的方法，有專家認(rèn)為，隨著基因解碼分析方法的采用，更多通過基因檢測未能找到病因的卵巢早衰患者可能會由于找到病因而得到更有針對性的治療。
四、POI病因
原發(fā)性卵巢功能不全可由遺傳缺陷、自身免疫性疾病、醫(yī)源性因素（化療或放療）、病毒感染或毒素引起，或者盡管進行了詳盡的調(diào)查，但仍可能是特發(fā)性的。遺傳缺陷，染色體異常和單基因缺陷可導(dǎo)致POI。同時，基因解碼也揭示，多個基因的共同作用，也可以導(dǎo)致卵巢早衰。本文試圖介紹卵巢早衰的基因解碼研究結(jié)果，以指導(dǎo)基因檢測進行得更為全面和有效。據(jù)透露，佳學(xué)基因等機構(gòu)正在著力研究不同基因?qū)е碌穆殉苍缢サ尼槍π哉{(diào)理方案，以便于更發(fā)的治療這種影響人類生育和生活水平的疾病。
A、 染色體異常與綜合征性卵巢早衰
染色體異常是卵巢早衰的一個公認(rèn)的原因，其發(fā)生率約為10-13%。染色體的數(shù)目變化主要發(fā)生在X單體（45，X；Turner綜合征）、鑲嵌型（45，X/46，XX和45，X/47，XXX），X三體（47，XXX），X缺失，X常染色體易位，以及或小或大的重排。通過細(xì)胞遺傳學(xué)分析可以對核型進行數(shù)值變化的評估，基因解碼倡導(dǎo)的全外顯子測序方法賊近已成為評估卵巢早衰I和其他內(nèi)分泌疾病的拷貝數(shù)變異（CNVs）的有力工具。此外，綜合征性卵巢早衰I也可能是由FMR1基因5'調(diào)節(jié)區(qū)的CGG重復(fù)序列的擴增引起的，這導(dǎo)致了脆性-X綜合征。在患者中，F(xiàn)MR1的CGG重復(fù)數(shù)大于200，由于該基因的甲基化和沉默，這種突變被稱為有效突變。對于動態(tài)突變患者，CGG重復(fù)數(shù)在55到199之間。在患有卵巢早衰的女性中，應(yīng)調(diào)查FMR1的動態(tài)突變，因為大約20%的女性攜帶者中，這種突變與卵巢早衰相關(guān)。此外，從Xq13.3到Xq27的X染色體區(qū)域被證明是卵巢功能正常的關(guān)鍵區(qū)域（卵巢早衰1[Xq23-Xq27]和POI2[Xq13-Xq21]）。此外，平衡X染色體易位斷點中斷的基因或X染色體點突變也是卵巢早衰的致病基因，這些基因包括包括COL4A6、DACH2、DIF2、NXF5、PGRMC1、POF1B和XPNPEP2。
B、 非綜合征性卵巢早衰：基因解碼所揭示的新卵巢早衰基因
B-1。已知卵巢早衰基因
卵巢發(fā)育和功能相關(guān)基因。在基因解碼時代，關(guān)于特發(fā)性卵巢早衰分子基礎(chǔ)的信息迅速增加。近年來，大規(guī)模測序技術(shù)已經(jīng)確定了一些已知基因的新致病性基因突變（FSHR、GDF9、BMP15、FIGLA和NOBOX）。這些基因首先與卵巢早衰的病因有關(guān)，因為它們在發(fā)育和/或卵巢功能中的作用。它們在功能上可分為與（1）生殖細(xì)胞發(fā)育相關(guān)的基因，（2）卵子發(fā)生和卵泡發(fā)生，（3）類固醇生成，和（4）激素信號傳導(dǎo)相關(guān)的基因。在胚胎發(fā)育過程中，大量的生殖細(xì)胞因為凋亡過程而消失，參與這一過程的基因突變，如nano3和EIF4ENIF1，可能導(dǎo)致卵巢早衰的發(fā)生。此外，許多因素參與卵泡和卵母細(xì)胞的募集、發(fā)育和成熟。事實上，編碼激素受體的基因突變，如FSHR和LHCGR，是卵巢功能損害的明顯原因，并可能在臨床上引起不同的疾病表征。卵巢功能正常的另一個重要步驟是類固醇生成，雌激素通過它合成。雌激素合成途徑的任何改變都可能導(dǎo)致閉經(jīng)和高FSH水平；然而，抗苗勒氏激素應(yīng)該是正常的。具有與類固醇生成途徑相關(guān)的基因突變的女性，如NR5A1和STAR，可能會出現(xiàn)綜合征或孤立的卵巢早衰表型。此外，生長因子如TGFβ家族成員（BMP15和GDF9）在卵巢功能中起著關(guān)鍵作用，這些基因的缺陷與卵巢早衰的發(fā)生有關(guān)。BMP15促進卵巢生長和成熟，可以以常染色體顯性遺傳和隱性遺傳的方式引起卵巢早衰表型（表1）。此外，GDF9蛋白對卵巢卵泡發(fā)育也是必不可少的，卵巢早衰患者出現(xiàn)繼發(fā)性閉經(jīng)的突變賊初被認(rèn)為是染色體顯性遺傳；然而，雜合子GDF9+/-雌性小鼠是可生育的，只有Gdf9陰性的雌性小鼠由于初級卵泡階段的阻塞而不育。這與之前觀察到的雜合子錯義突變不同?；蚪獯a研究人員一名巴西原發(fā)性閉經(jīng)患者中發(fā)現(xiàn)了GDF9基因的純合子1-bp缺失（c.783delC）突變，這是一種更嚴(yán)重的表型。在過去的二十年中，一些與人類和動物模型中的出生后卵母細(xì)胞分化相關(guān)的轉(zhuǎn)錄因子被相繼確定，如NOBOX、SOHLH1、SOHLH2、FIGLA和LHX8。NOBOX能夠調(diào)節(jié)多種卵巢基因，包括GDF9和BMP15。在小鼠中，NOBOX蛋白的缺失會導(dǎo)致原始卵泡的逐漸喪失，從而導(dǎo)致成熟卵泡的缺失。賊初，描述了具有顯性負(fù)效應(yīng)的雜合子致病基因突變，但是也觀察到一個純合變異的家族病例；一名中國患者也出現(xiàn)了原發(fā)性閉經(jīng)。SOHLH1在卵泡發(fā)育的初始階段[參與生殖細(xì)胞的維持。在人類中，SOHLH1的雙等位基因突變在兩個患有孤立性POI的家族中被鑒定出來。非綜合征卵巢早衰還與FIGLA基因雜合缺失有關(guān)，F(xiàn)IGLA基因是螺旋-環(huán)-螺旋家族的一種轉(zhuǎn)錄因子。這種轉(zhuǎn)錄因子調(diào)節(jié)透明帶中基因的表達(dá)以及其他僅在卵巢中表達(dá)的基因；因此，它的缺失或缺陷可能會促進人類和小鼠的卵巢功能衰竭。
減數(shù)分裂和DNA修復(fù)基因。基因解碼普遍采用高通量測序技術(shù)全面獲得可能引起患者各種復(fù)雜表型的致病基因突變，從而揭示了主要在細(xì)胞分裂和/或DNA修復(fù)中起重要作用的新基因，這些基因包括MCM8、MCM9、STAG3、PSMC3IP、HFM1、NUP107和SYCE1）。卵母細(xì)胞在出生前開始減數(shù)分裂的先進階段，在胎兒期停留在先進階段，當(dāng)婦女進入青春期時重新開始細(xì)胞分裂；次級卵母細(xì)胞在排卵時釋放。由于卵母細(xì)胞處于靜息狀態(tài)，參與減數(shù)分裂和DNA修復(fù)的基因改變可能導(dǎo)致卵巢功能不全的不同表型。一些輔酶，如STAG3和Syc1，在細(xì)胞分裂過程中對突觸復(fù)合體的正確形成是必不可少的，這些基因的突變導(dǎo)致人類不育。此外，小染色體維持蛋白（MCM8和MCM9）的解旋酶在減數(shù)分裂期間的同源重組步驟中起著至關(guān)重要的作用。MCM8和MCM9蛋白的缺失促進了小鼠減數(shù)分裂過程中的錯誤，例如MCM8-/-小鼠的減數(shù)分裂前期I停止、初級卵泡停止、卵巢腫瘤的頻繁發(fā)生，以及MCM9-/-小鼠有效缺乏卵母細(xì)胞。在過去的幾年中，導(dǎo)致MCM8和MCM9蛋白質(zhì)功能喪失的純合突變被以高通量測序為基礎(chǔ)條件的基因解碼分析方法不斷被鑒定明確下來。
B-2號?；蚪獯a揭示的新基因
此外，在人類和動物模型中，與卵巢發(fā)育和減數(shù)分裂有關(guān)的卵巢早衰的新病因至少有15個。這些基因按照與卵巢早衰相關(guān)的已知基因的相同模式進行分類。
卵巢發(fā)育和功能相關(guān)基因：BMP受體2（BMPR2）。BMPR2是一種絲氨酸蘇氨酸激酶II型受體，它似乎結(jié)合BMP因子來影響其配體的下游信號傳導(dǎo)，影響卵泡發(fā)育。Patiño及其合作者報告了體外證據(jù)，證明BMPR2中的p.Ser987Phe突變增加了內(nèi)質(zhì)網(wǎng)的亞細(xì)胞聚集模式，顯示了該基因與分離的卵巢早衰有潛在的關(guān)聯(lián)。
縫隙連接蛋白α4（GJA4）/連接蛋白-37（CX37）。GJA4在卵泡發(fā)育中起作用，在小鼠體內(nèi)該基因的破壞導(dǎo)致卵巢卵泡發(fā)生在腔前階段停止，從而導(dǎo)致女性不育。在2例繼發(fā)性閉經(jīng)的卵巢早衰患者中發(fā)現(xiàn)GJA4中的雜合子錯義變體（c.946G>A:p.Gly316Ser）。雖然這種突變在白種人的對照組中還沒有報道，但在非洲個體中普遍觀察到。體外研究表明，p.Gly316Ser能夠以顯性陰性的方式降低細(xì)胞表面縫隙連接斑塊的表達(dá)。其機制可能涉及縫隙連接內(nèi)吞和溶酶體降解的增加。事實上，在這個法國隊列中進行了候選基因研究；因此，沒有其他POI候選基因被排除為POI的原因。
含RNA結(jié)合信號轉(zhuǎn)導(dǎo)相關(guān)蛋白1（KHDRBS1）的KH結(jié)構(gòu)域。KHDRBS1在多種細(xì)胞過程中發(fā)揮作用，如選擇性剪接、細(xì)胞周期調(diào)控、RNA 3′端形成、腫瘤發(fā)生和人類免疫系統(tǒng)調(diào)節(jié)。KHDRBS1（又名Sam68）在敲除雌性小鼠卵巢中的作用已被研究。Sam68-/-雌性小鼠由于先進次懷孕延遲、產(chǎn)仔量少、卵巢中次級卵泡和腔前卵泡數(shù)量減少而表現(xiàn)出低生育能力[98]。利用全外顯子組測序（WES），在一名中國母親和一名患POI的大女兒中發(fā)現(xiàn)了一個KHDRBS1雜合子變異（c.460A>G:p.Met154Val）。在另一名患者中也發(fā)現(xiàn)了第二個單等位基因突變（c.263C>T:p.Pro88Leu）。體外試驗表明KHDRBS1突變（c.460A>G）對選擇性剪接的影響；然而，還沒有進行體內(nèi)研究[98]。KHDRBS1的另一個雜合子變體（c.887C>T:p.Pro296Leu）也在一名攜帶FGFR2變體的POI患者中發(fā)現(xiàn)（c.64C>T:p.Arg22Trp）[99]。然而，需要進一步的功能研究來驗證其致病性。
自噬相關(guān)蛋白7（ATG7）和自噬相關(guān)蛋白9（ATG9A）。自噬是一種適應(yīng)過程，發(fā)生在對不同形式的應(yīng)激反應(yīng)中，如營養(yǎng)缺乏、生長因子耗竭、感染和缺氧。自噬過程調(diào)節(jié)許多疾病，包括神經(jīng)退行性疾病、癌癥和傳染病[100]。自噬因子，如自噬相關(guān)蛋白（ATG）及其調(diào)節(jié)因子，對自噬過程至關(guān)重要，包括起始、吞噬細(xì)胞成核和膨脹（ATG7和ATG9）、貨物隔離、膜密封、自噬體成熟和自噬體與溶酶體融合[100]。小鼠缺乏Atg7會導(dǎo)致中樞神經(jīng)系統(tǒng)功能受損，導(dǎo)致出生后28周出現(xiàn)行為缺陷和致死性?；蚯贸∈蟠竽X和小腦皮質(zhì)也有大量神經(jīng)元丟失[101]。此外，由于自噬機制的缺陷，卵巢中原始卵泡減少，生殖細(xì)胞特異性敲除Atg7促進了雌性小鼠的亞生育能力[102]。在雄性小鼠中，Atg7的破壞會導(dǎo)致頂體的異常形成和異常圓頭精子的發(fā)育[103]，從而導(dǎo)致生育能力低下。Atg9條件敲除小鼠表現(xiàn)出神經(jīng)功能缺陷，包括軸突及其終末的進行性變性，但不包括神經(jīng)元細(xì)胞體，這些小鼠在出生后4周內(nèi)死亡[104]。在人類中，在兩名分別被診斷為繼發(fā)性和原發(fā)性閉經(jīng)的患者中，ATG7（c.1209T>A:p.Phe403Leu）和ATG9（c.2272C>T:p.Arg758Cys）有兩個單等位基因突變[10,90]。在體外研究中，這些突變通過降低產(chǎn)生自噬體的能力，以單體不足的方式破壞自噬過程[90]。
RNA聚合酶III亞單位H（POLR3H）。RNA聚合酶III合成一些未翻譯的RNA，并在細(xì)胞生長、分化和先天免疫反應(yīng)中發(fā)揮關(guān)鍵作用[105]。盡管亞單位A和B（POLR3A和POLR3B）與隱性4H綜合征（包括髓鞘發(fā)育不良、牙髓發(fā)育不良、促性腺激素低下和白質(zhì)營養(yǎng)不良綜合征）相關(guān)，但在人類疾病的情況下，尚未報告該亞基的突變，甚至是孤立的促性腺激素低下癥[109]。
我們之前報道了兩個POI不相關(guān)家系中POLR3H中的一個新的雙等位基因錯義突變（c.149A>G:p.Asp50Gly），并用CRISPR/Cas9方法生成了兩個小鼠系，以評估POLR3H-p.Asp50Gly突變的內(nèi)在機制[93]。在具有Polr3hD50G突變的小鼠中觀察到早期胚胎致死性[93]。與所有4例患者一樣，攜帶Polr3hD50G純合子點突變的小鼠表現(xiàn)出青春期延遲。在Polr3hD50G雌性和雄性小鼠中觀察到產(chǎn)仔量小，懷孕時間或懷孕時間增加。的確，與野生型小鼠相比，Polr3hD50G小鼠卵巢Foxo3a表達(dá)減少，初級卵泡數(shù)量更少[93]。這是POLR3H致病性突變導(dǎo)致人類不孕的進步證據(jù)。
切口受體2（NOTCH2）。NOTCH通路參與了胎兒和出生后的細(xì)胞命運決定和分化過程[110]。相關(guān)的蛋白質(zhì)，包括四個NOTCH受體（NOTCH 1-4）和5個NOTCH配體（鋸齒狀1-2和DELTA-LIKE 1、3和4），與無脊椎動物（果蠅、秀麗隱桿線蟲）和哺乳動物自我更新系統(tǒng)的穩(wěn)態(tài)維持有關(guān)[110]。NOTCH信號在調(diào)節(jié)原始卵泡形成中的功能作用已在小鼠中得到證實[111]。在NOTCH信號抑制劑的存在下，新生卵巢的原始卵泡減少。研究還表明jagg-1、NOTCH2和HES1分別是表達(dá)賊豐富的配體、受體和靶基因。此外，NOTCH2在原始卵泡的顆粒前細(xì)胞中表達(dá)[111]。在人類中，NOTCH2與Alagille綜合征（ALGS）相關(guān)，這是一種常染色體顯性多系統(tǒng)疾病，臨床定義為肝膽管貧乏和膽汁淤積，并伴有心臟、骨骼和眼科表現(xiàn)（MIM-118450）。此外，Hajdu-Cheney綜合征（HJCYS）也與NOTCH2有關(guān)，是一種罕見的常染色體顯性骨骼疾病，其特征是身材矮小、相貌粗糙和畸形、長骨彎曲和脊椎畸形（MIM-102500）。
賊近報道了與POI相關(guān)的NOTCH2突變。已鑒定出4例具有不同NOTCH2變異體的患者：1例患者出現(xiàn)原發(fā)性閉經(jīng)，并攜帶復(fù)合雜合子突變（c[7223T>a:p.Leu2408His]；[6947C>T:p.Ala2316Val]），3例患者出現(xiàn)繼發(fā)性閉經(jīng)，每個患者都攜帶一個單等位基因變體（c.5411C>T:p.Ser1804Leu，c.7075C>G:p.Pro2359Ala，或c、 5433G>c:p.Gln1811His）。上述3個NOTCH2突變（p.Ser1804Leu、p.Ala2316Val和p.Pro2359Ala）的轉(zhuǎn)錄活性已經(jīng)得到證實，盡管在對照組和具有所有所述突變體的個體之間沒有蛋白質(zhì)水平的差異[94]。
減數(shù)分裂和DNA修復(fù)基因：參與DNA修復(fù)的支架蛋白（SPIDR/KIAA0146）。SPIDR是一種連接解旋酶和同源重組（HR）機制的蛋白質(zhì)。SPIDR的缺失促進了姐妹染色單體缺陷、基因組不穩(wěn)定性和對DNA損傷效應(yīng)的敏感性的增加[112]。在2個有POI的姐妹中發(fā)現(xiàn)了一個無意義的純合突變（c.839G>A:p.Trp280*），其父母為以色列-穆斯林-阿拉伯血統(tǒng)。這對姐妹表現(xiàn)為青春期延遲，促性腺激素水平升高，臨床表現(xiàn)有一些差異，包括卵巢發(fā)育不全和咖啡色斑（妹妹）或卵巢缺失（姐姐）。兩姐妹的核型正常，46，XX，無畸形特征。p.Trp280*突變表明，SPIDR活性在同源重組過程中受損，導(dǎo)致53BP1標(biāo)記的雙鏈斷裂，并在未受干擾的生長過程中造成gH2AX標(biāo)記的損傷[80]。
MutS同系物4（MSH4）和MutS同源物5（MSH5）。MSH4和MSH5是減數(shù)分裂特異性蛋白，是同源染色體重組和正確分離所必需的。攜帶Msh4或Msh5缺陷的雄性和雌性小鼠由于減數(shù)分裂失敗而不育[113114]，這兩種基因都可能參與POI的發(fā)病機制。診斷為繼發(fā)性閉經(jīng)的兩個姐妹被發(fā)現(xiàn)在MSH4中存在純合供體剪接位點突變（c.2355+1G>a:p.Ile743_Lys785del）[81]。在一個中國隊列中，在2個分離的POI姐妹中發(fā)現(xiàn)了一個新的MSH5純合子錯義突變（c.1459G>T:p.Asp487Tyr）。在一項體外研究中，使用敲除小鼠（Msh5D486Y/D486Y）進行的功能評估顯示卵巢萎縮，MSH5破壞損害了DNA同源重組修復(fù)[82]。
范科尼貧血互補組（fancom）。FANCM參與修復(fù)DNA復(fù)制和同源重組。這種基因的單等位基因突變與乳腺癌和卵巢癌的易感性有關(guān)。此外，由于缺乏遺傳數(shù)據(jù)或其他功能證據(jù)，F(xiàn)ANCM不再被列為Fanconi貧血基因，雙等位基因突變在該疾病中起著重要作用[115]。然而，在兩個被診斷為非綜合征性POI的芬蘭同胞中發(fā)現(xiàn)了FANCM的純合無義突變（c.5101C>T:p.Gln1701*）。對姐妹的淋巴細(xì)胞分析顯示，染色體斷裂和對絲裂霉素C過敏的程度增加[84]。此外，在一名被診斷患有無精子癥的葡萄牙人身上發(fā)現(xiàn)了FANCM的雙等位基因突變（c.5791C>T:p.Arg1931*）。FANCM突變已被證明與減數(shù)分裂缺陷和男性不育有關(guān)。
巴索諾克林1號（BNC1）。BNC1是一種鋅指蛋白，在睪丸和卵巢的生殖細(xì)胞、角質(zhì)形成細(xì)胞和毛囊中高度表達(dá)。敲除小鼠卵母細(xì)胞中的BNC1可降低RNA聚合酶的轉(zhuǎn)錄水平，并導(dǎo)致小而不規(guī)則的卵泡形態(tài)。事實上，敲除卵巢顯示黃體呈現(xiàn)正常排卵，盡管女性出現(xiàn)亞生育[117]。用WES方法對一個有7例POI感染婦女的中國家庭進行篩查，發(fā)現(xiàn)BNC1基因有5-bp的雜合子缺失（c.1065_1069）交貨：p.Arg356Valfs*6） 一。此外，在4例無關(guān)的POI患者中發(fā)現(xiàn)了BNC1的雜合子錯義變體（c.1595T>c:p.Leu532Pro）[88]。在體外和體內(nèi)實驗中證實了BNC1半抗原的不足。有缺失和錯義突變的轉(zhuǎn)染細(xì)胞在卵巢中表現(xiàn)出異常的核定位和減數(shù)分裂的損傷。攜帶5-bp缺失的雜合子（Bnc1+/-）和純合子（Bnc1-/-）小鼠由于卵巢儲備減少（即FSH升高、卵巢大小減小和卵泡大小減小）而表現(xiàn)出雌性不育[88]。
含蛋白62的WD重復(fù)序列（WDR62）。WDR62是一種廣泛表達(dá)的支架JNK結(jié)合蛋白。這種蛋白在應(yīng)激后的mRNA穩(wěn)態(tài)中起著調(diào)節(jié)作用，JNK是它的伙伴[118]。Bilguvar及其合作者[119]首先在10名患者中發(fā)現(xiàn)了WDR62的隱性錯義和功能缺失突變，并發(fā)現(xiàn)這些突變導(dǎo)致了廣泛的大腦皮質(zhì)畸形，包括小頭畸形、皮質(zhì)增厚的厚皮癥和胼胝體發(fā)育不全。后來，由于有絲分裂缺陷、神經(jīng)元遷移延遲和神經(jīng)元分化改變，在神經(jīng)發(fā)生過程中，Wdr62的破壞導(dǎo)致了小頭癥。這些老鼠也是不育的，并且在出生后的早期階段體型比正常老鼠小[120]。此外，Wdr62基因敲除小鼠表現(xiàn)出雌性減數(shù)分裂起始缺陷，這些缺陷通過JNK1在生殖細(xì)胞中的過度表達(dá)得以挽救，呈現(xiàn)卵巢減少和卵泡缺失的不孕癥[89]。利用WES，研究人員還評估了兩例診斷為原發(fā)性閉經(jīng)的散發(fā)性POI病例，每個病例都有一個錯義突變（c.1796G>A:p.Cys599Tyr）或一個移碼突變（c.3203_3206）交貨：p.Thr1068fs)在WDR62中。盡管體外研究表明，這些突變的顯性負(fù)效應(yīng)受Stra8表達(dá)的調(diào)控，并且小鼠表型與原發(fā)性閉經(jīng)表型相關(guān)，攜帶p.Cys599Tyr突變的患者在2個與女性不育相關(guān)的不同基因（BRCA2和SPTB）中也有3個額外的變體；因此，該患者的遺傳病因仍不清楚[89]。
DNA修復(fù)相關(guān)/乳腺癌2型易感蛋白/范科尼貧血組D1蛋白（BRCA2）。BRCA2參與維持基因組的穩(wěn)定性，特別是雙鏈DNA修復(fù)的同源重組途徑的信號傳導(dǎo)[121]。Davies及其合作者[122]表明，BRCA2在調(diào)節(jié)RAD51（一種同源重組和DNA修復(fù)所必需的蛋白質(zhì)）的作用中起著雙重作用。因此，BRCA2失活后失去對這些過程的控制可能導(dǎo)致基因組不穩(wěn)定和腫瘤發(fā)生[122]。BRCA2（和BRCA1）的種系單等位基因突變增加了終生癌癥的風(fēng)險；它們首先被描述為家族性病例中的乳腺癌和卵巢癌，其次是散發(fā)病例，后來是男性乳腺癌和前列腺癌病例[123]。此外，D1型范科尼貧血是由BRCA2純合突變引起的。男性和女性患者有多種先天性異常、骨髓衰竭和預(yù)期的癌癥易感性。在這些患者中，通常包括更年期男性的精子發(fā)生改變。非血緣埃塞俄比亞父母所生的兩個姐妹被診斷為POI，表現(xiàn)為原發(fā)性閉經(jīng)、青春期延遲、身材矮小、咖啡色斑、小頭畸形，其中一個姐妹的急性髓細(xì)胞白血病長期緩解[91]。這些兄弟姐妹攜帶BRCA2的復(fù)合雜合子截斷突變（約7579德爾格：p.Val2527*]和[9693德拉：p.Ser3231fs16*]). 有趣的是，分離分析顯示在他們的母親中有一個單等位基因BRCA2突變（c.7579delG），診斷為卵巢癌Ⅲ期患者。先證者外周血淋巴細(xì)胞染色體斷裂，以及RAD51基因未能進入雙鏈DNA斷裂，表明對DNA損傷的反應(yīng)受損。此外，果蠅BRCA2同源體的破壞導(dǎo)致雄性和雌性不育和性腺發(fā)育不全[91]。其中1例為散發(fā)性突變，其中1例為家族性突變交貨：p.Cys3233Trpfs*15] ），分別為[92]。這些病人表現(xiàn)為原發(fā)性閉經(jīng)，但沒有發(fā)現(xiàn)血液學(xué)異常或腫瘤。另外，2個姐妹表現(xiàn)為原發(fā)性閉經(jīng)和小頭畸形，被診斷為早發(fā)性結(jié)直腸癌和乳腺癌。BRCA2的兩個變體（c.[6468_6469delTC]；[c.8471G>c]）在兩個兄弟姐妹中都被發(fā)現(xiàn)，隨后通過長程PCR證實為反式[92]。雖然賊后2例可能擴大了BRCA2表型的范圍，但其致病性需要進一步的功能驗證。
腫瘤蛋白p63（TP63）。TP63是p53家族的一員，是一種與癌癥、發(fā)育和生殖有關(guān)的轉(zhuǎn)錄因子[124]。p63和p73的聯(lián)合丟失損害了p53依賴性凋亡的誘導(dǎo)，以響應(yīng)小鼠胚胎成纖維細(xì)胞的DNA損傷和體內(nèi)方法[125]。此外，p63，特別是TAp63亞型，通過調(diào)節(jié)DICER和miR130b來抑制腫瘤的發(fā)生和轉(zhuǎn)移[126]。在卵巢中，p63被要求在減數(shù)分裂停止期間維持雌性生殖系的完整性。此外，p63在DNA損傷誘導(dǎo)的初級卵母細(xì)胞死亡過程中起著關(guān)鍵作用，不涉及p53[126]。p63缺失小鼠的卵母細(xì)胞對殺死WT和p53空白小鼠所有卵母細(xì)胞的相同劑量的輻射具有抵抗力[126]。TP63與通過常染色體顯性遺傳（MIM 603273）影響多個器官的復(fù)雜綜合征有關(guān)；然而，賊近在一個表現(xiàn)為原發(fā)性閉經(jīng)的孤立POI患者中發(fā)現(xiàn)TP63中的1個單等位基因無意義致病性變體（c.1794G>A:p.Arg594*）。需要進一步的功能研究來評估這種變體的致病性。
代謝和蛋白質(zhì)合成相關(guān)基因：RNA聚合酶II亞單位C（POLR2C）。POLR2C編碼RNA聚合酶II的賊大亞單位，在真核生物中合成信使RNA[127]。在一名患有家族性POI的婦女中發(fā)現(xiàn)了POLR2C的雜合子無義突變（c.454A>T:p.Lys152*），她還被診斷為免疫性血小板減少癥、惡性貧血和甲狀腺功能減退。一項含有p.Lys152*基因敲除的體外研究顯示POLR2C水平降低，細(xì)胞增殖受損[85]。
五、總結(jié)
POI是一種高度異質(zhì)性的疾病，與75個以上的基因突變有關(guān)，這些基因主要與減數(shù)分裂和DNA修復(fù)有關(guān)，每一個基因只影響少數(shù)女性。一些基因還沒有被證明與POI病因?qū)W有關(guān)，功能研究或關(guān)于受累婦女的額外報告有理由證實它們與POI病因的關(guān)系。雖然POI的遺傳病因?qū)W已經(jīng)被幾個小組研究過，盡管NGS技術(shù)已經(jīng)增加了在POI病因?qū)W中起作用的已知基因的數(shù)量，并且允許在POI病因?qū)W中發(fā)現(xiàn)新的參與者，但是大多數(shù)病例仍然沒有明確的基因診斷。在接下來的幾年里，考慮到這種疾病強大的遺傳背景和低成本、高通量的并行測序技術(shù)的廣泛應(yīng)用，將發(fā)現(xiàn)POI表型的新的遺傳病因。
卵巢早衰基因解碼已發(fā)表的證據(jù)支持
1.
Hewitt GD, Gerancher KR. ACOG Committee Opinion No. 760: Dysmenorrhea and Endometriosis in the Adolescent. Obstet Gynecol. Obstetr Gynecol. 2018;132(6):E249–E258. [PubMed] [Google Scholar]
2.
Webber L, Davies M, Anderson R, et al. . ESHRE guideline: management of women with premature ovarian insufficiency. Hum Reprod. 2016;31(5):926–937. [PubMed] [Google Scholar]
3.
Albright F, Smith PH, Fraser R.. A syndrome characterized by primary ovarian insufficiency and decreased stature: report of 11 cases with a digression on hormonal control of axillary and pubic hair. Am J Med Sci. 1942;204:625–648. [Google Scholar]
4.
Tucker EJ, Grover SR, Bachelot A, Touraine P, Sinclair AH. Premature ovarian insufficiency: new perspectives on genetic cause and phenotypic spectrum. Endocr Rev. 2016;37(6):609–635. [PubMed] [Google Scholar]
5.
Franca MM, FM, Lerario AM, et al. . Screening of targeted panel genes in 50 Brazilian patients with primary ovarian insufficiency. 2019.
6.
Goswami D, Conway GS. Premature ovarian failure. Hum Reprod Update. 2005;11(4):391–410. [PubMed] [Google Scholar]
7.
Lagergren K, Hammar M, Nedstrand E, Bladh M, Sydsjö G. The prevalence of primary ovarian insufficiency in Sweden; a national register study. BMC Womens Health. 2018;18(1):175. [PMC free article] [PubMed] [Google Scholar]
8.
Luborsky JL, Meyer P, Sowers MF, Gold EB, Santoro N. Premature menopause in a multi-ethnic population study of the menopause transition. Hum Reprod. 2003;18(1):199–206. [PubMed] [Google Scholar]
9.
Fonseca DJ, Patiño LC, Suárez YC, et al. . Next generation sequencing in women affected by nonsyndromic premature ovarian failure displays new potential causative genes and mutations. Fertil Steril. 2015;104(1):154–162.e2. [PubMed] [Google Scholar]
10.
Patiño LC, Silgado D, Laissue P. A potential functional association between mutant BMPR2 and primary ovarian insufficiency. Syst Biol Reprod Med. 2017;63(3):145–149. [PubMed] [Google Scholar]
11.
Qin Y, Jiao X, Simpson JL, Chen ZJ. Genetics of primary ovarian insufficiency: new developments and opportunities. Hum Reprod Update. 2015;21(6):787–808. [PMC free article] [PubMed] [Google Scholar]
12.
Bestetti I, Castronovo C, Sironi A, et al. . High-resolution array-CGH analysis on 46,XX patients affected by early onset primary ovarian insufficiency discloses new genes involved in ovarian function. Hum Reprod. 2019;34(3):574–583. [PMC free article] [PubMed] [Google Scholar]
13.
Funari MFA, de Barros JS, Santana LS, et al. . Evaluation of SHOX defects in the era of next-generation sequencing. Clin Genet. 2019;96(3):261–265. [PubMed] [Google Scholar]
14.
Sullivan SD, Welt C, Sherman S. FMR1 and the continuum of primary ovarian insufficiency. Semin Reprod Med. 2011;29(4):299–307. [PubMed] [Google Scholar]
15.
Nishimura-Tadaki A, Wada T, Bano G, et al. . Breakpoint determination of X;autosome balanced translocations in four patients with premature ovarian failure. J Hum Genet. 2011;56(2):156–160. [PubMed] [Google Scholar]
16.
Bione S, Sala C, Manzini C, et al. . A human homologue of the Drosophila melanogaster diaphanous gene is disrupted in a patient with premature ovarian failure: evidence for conserved function in oogenesis and implications for human sterility. Am J Hum Genet. 1998;62(3):533–541. [PMC free article] [PubMed] [Google Scholar]
17.
Bione S, Rizzolio F, Sala C, et al. . Mutation analysis of two candidate genes for premature ovarian failure, DACH2 and POF1B. Hum Reprod. 2004;19(12):2759–2766. [PubMed] [Google Scholar]
18.
Genesio R, Mormile A, Licenziati MR, et al. . Short stature and primary ovarian insufficiency possibly due to chromosomal position effect in a balanced X;1 translocation. Mol Cytogenet. 2015;8:50. [PMC free article] [PubMed] [Google Scholar]
19.
Bertini V, Ghirri P, Bicocchi MP, Simi P, Valetto A. Molecular cytogenetic definition of a translocation t(X;15) associated with premature ovarian failure. Fertil Steril. 2010;94(3):1097.e5–1097.e8. [PubMed] [Google Scholar]
20.
Chen CP, Su YN, Lin HH, et al. . De novo duplication of Xq22.1→q24 with a disruption of the NXF gene cluster in a mentally retarded woman with short stature and premature ovarian failure. Taiwan J Obstet Gynecol. 2011;50(3):339–344. [PubMed] [Google Scholar]
21.
Mansouri MR, Schuster J, Badhai J, et al. . Alterations in the expression, structure and function of progesterone receptor membrane component-1 (PGRMC1) in premature ovarian failure. Hum Mol Genet. 2008;17(23):3776–3783. [PMC free article] [PubMed] [Google Scholar]
22.
Lorda-Sanchez IJ, Ibañez AJ, Sanz RJ, et al. . Choroideremia, sensorineural deafness, and primary ovarian failure in a woman with a balanced X-4 translocation. Ophthalmic Genet. 2000;21(3):185–189. [PubMed] [Google Scholar]
23.
Lacombe A, Lee H, Zahed L, et al. . Disruption of POF1B binding to nonmuscle actin filaments is associated with premature ovarian failure. Am J Hum Genet. 2006;79(1):113–119. [PMC free article] [PubMed] [Google Scholar]
24.
Ledig S, Preisler-Adams S, Morlot S, Liehr T, Wieacker P. Premature ovarian failure caused by a heterozygous missense mutation in POF1B and a reciprocal translocation 46,X,t(X;3)(q21.1;q21.3). Sex Dev. 2015;9(2):86–90. [PubMed] [Google Scholar]
25.
Prueitt RL, Chen H, Barnes RI, Zinn AR. Most X;autosome translocations associated with premature ovarian failure do not interrupt X-linked genes. Cytogenet Genome Res. 2002;97(1-2):32–38. [PubMed] [Google Scholar]
26.
Dixit H, Rao LK, Padmalatha V, et al. . Mutational screening of the coding region of growth differentiation factor 9 gene in Indian women with ovarian failure. Menopause. 2005;12(6):749–754. [PubMed] [Google Scholar]
27.
França MM, Funari MFA, Nishi MY, et al. . Identification of the first homozygous 1-bp deletion in GDF9 gene leading to primary ovarian insufficiency by using targeted massively parallel sequencing. Clin Genet. 2018;93(2):408–411. [PubMed] [Google Scholar]
28.
Di Pasquale E, Beck-Peccoz P, Persani L. Hypergonadotropic ovarian failure associated with an inherited mutation of human bone morphogenetic protein-15 (BMP15) gene. Am J Hum Genet. 2004;75(1):106–111. [PMC free article] [PubMed] [Google Scholar]
29.
Patiño LC, Walton KL, Mueller TD, et al. . BMP15 mutations associated with primary ovarian insufficiency reduce expression, activity, or synergy with GDF9. J Clin Endocrinol Metab. 2017;102(3):1009–1019. [PubMed] [Google Scholar]
30.
Zhang W, Wang J, Wang X, et al. . A novel homozygous mutation of bone morphogenetic protein 15 identified in a consanguineous marriage family with primary ovarian insufficiency. Reprod Biomed Online. 2018;36(2):206–209. [PubMed] [Google Scholar]
31.
Mayer A, Fouquet B, Pugeat M, Misrahi M. BMP15 “knockout-like” effect in familial premature ovarian insufficiency with persistent ovarian reserve. Clin Genet. 2017;92(2):208–212. [PubMed] [Google Scholar]
32.
Qin Y, Choi Y, Zhao H, Simpson JL, Chen ZJ, Rajkovic A. NOBOX homeobox mutation causes premature ovarian failure. Am J Hum Genet. 2007;81(3):576–581. [PMC free article] [PubMed] [Google Scholar]
33.
Li L, Wang B, Zhang W, et al. . A homozygous NOBOX truncating variant causes defective transcriptional activation and leads to primary ovarian insufficiency. Hum Reprod. 2017;32(1):248–255. [PubMed] [Google Scholar]
34.
França MM, Funari MFA, Lerario AM, et al. . A novel homozygous 1-bp deletion in the NOBOX gene in two Brazilian sisters with primary ovarian failure. Endocrine. 2017;58(3):442–447. [PubMed] [Google Scholar]
35.
Zhao H, Chen ZJ, Qin Y, et al. . Transcription factor FIGLA is mutated in patients with premature ovarian failure. Am J Hum Genet. 2008;82(6):1342–1348. [PMC free article] [PubMed] [Google Scholar]
36.
Chen B, Li L, Wang J, et al. . Consanguineous familial study revealed biallelic FIGLA mutation associated with premature ovarian insufficiency. J Ovarian Res. 2018;11(1):48. [PMC free article] [PubMed] [Google Scholar]
37.
Yuan P, He Z, Sun S, et al. . Bi-allelic recessive loss-of-function mutations in FIGLA cause premature ovarian insufficiency with short stature. Clin Genet. 2019;95(3):409–414. [PubMed] [Google Scholar]
38.
Aittomäki K, Lucena JL, Pakarinen P, et al. . Mutation in the follicle-stimulating hormone receptor gene causes hereditary hypergonadotropic ovarian failure. Cell. 1995;82(6):959–968. [PubMed] [Google Scholar]
39.
França MM, Lerario AM, Funari MFA, et al. . A novel homozygous missense FSHR variant associated with hypergonadotropic hypogonadism in two siblings from a Brazilian family. Sex Dev. 2017;11(3):137–142. [PubMed] [Google Scholar]
40.
Liu H, Xu X, Han T, et al. . A novel homozygous mutation in the FSHR gene is causative for primary ovarian insufficiency. Fertil Steril. 2017;108(6):1050–1055.e2. [PubMed] [Google Scholar]
41.
He WB, Du J, Yang XW, et al. . Novel inactivating mutations in the FSH receptor cause premature ovarian insufficiency with resistant ovary syndrome. Reprod Biomed Online. 2019;38(3):397–406. [PubMed] [Google Scholar]
42.
Liu H, Guo T, Gong Z, et al. . Novel FSHR mutations in Han Chinese women with sporadic premature ovarian insufficiency. Mol Cell Endocrinol. 2019;492:110446. [PubMed] [Google Scholar]
43.
Santos MG, Machado AZ, Martins CN, et al. . Homozygous inactivating mutation in NANOS3 in two sisters with primary ovarian insufficiency. Biomed Res Int. 2014;2014:787465. [PMC free article] [PubMed] [Google Scholar]
44.
Kasippillai T, MacArthur DG, Kirby A, et al. . Mutations in eIF4ENIF1 are associated with primary ovarian insufficiency. J Clin Endocrinol Metab. 2013;98(9):E1534–E1539. [PMC free article] [PubMed] [Google Scholar]
45.
Arnhold IJ, Lofrano-Porto A, Latronico AC. Inactivating mutations of luteinizing hormone beta-subunit or luteinizing hormone receptor cause oligo-amenorrhea and infertility in women. Horm Res. 2009;71(2):75–82. [PubMed] [Google Scholar]
46.
Lourenço D, Brauner R, Lin L, et al. . Mutations in NR5A1 associated with ovarian insufficiency. N Engl J Med. 2009;360(12):1200–1210. [PMC free article] [PubMed] [Google Scholar]
47.
Bose HS, Pescovitz OH, Miller WL. Spontaneous feminization in a 46,XX female patient with congenital lipoid adrenal hyperplasia due to a homozygous frameshift mutation in the steroidogenic acute regulatory protein. J Clin Endocrinol Metab. 1997;82(5):1511–1515. [PubMed] [Google Scholar]
48.
Peng J, Li Q, Wigglesworth K, et al. . Growth differentiation factor 9:bone morphogenetic protein 15 heterodimers are potent regulators of ovarian functions. Proc Natl Acad Sci U S A. 2013;110(8):E776–E785. [PMC free article] [PubMed] [Google Scholar]
49.
Chang H, Brown CW, Matzuk MM. Genetic analysis of the mammalian transforming growth factor-beta superfamily. Endocr Rev. 2002;23(6):787–823. [PubMed] [Google Scholar]
50.
Laissue P, Christin-Maitre S, Touraine P, et al. . Mutations and sequence variants in GDF9 and BMP15 in patients with premature ovarian failure. Eur J Endocrinol. 2006;154(5):739–744. [PubMed] [Google Scholar]
51.
Kovanci E, Rohozinski J, Simpson JL, Heard MJ, Bishop CE, Carson SA. Growth differentiating factor-9 mutations may be associated with premature ovarian failure. Fertil Steril. 2007;87(1):143–146. [PubMed] [Google Scholar]
52.
Dong J, Albertini DF, Nishimori K, Kumar TR, Lu N, Matzuk MM. Growth differentiation factor-9 is required during early ovarian folliculogenesis. Nature. 1996;383(6600):531–535. [PubMed] [Google Scholar]
53.
Rajkovic A, Pangas SA, Ballow D, Suzumori N, Matzuk MM. NOBOX deficiency disrupts early folliculogenesis and oocyte-specific gene expression. Science. 2004;305(5687):1157–1159. [PubMed] [Google Scholar]
54.
Ballow D, Meistrich ML, Matzuk M, Rajkovic A. Sohlh1 is essential for spermatogonial differentiation. Dev Biol. 2006;294(1):161–167. [PubMed] [Google Scholar]
55.
Bayram Y, Gulsuner S, Guran T, et al. . Homozygous loss-of-function mutations in SOHLH1 in patients with nonsyndromic hypergonadotropic hypogonadism. J Clin Endocrinol Metab. 2015;100(5):E808–E814. [PMC free article] [PubMed] [Google Scholar]
56.
Ballow DJ, Xin Y, Choi Y, Pangas SA, Rajkovic A. Sohlh2 is a germ cell-specific bHLH transcription factor. Gene Expr Patterns. 2006;6(8):1014–1018. [PubMed] [Google Scholar]
57.
Choi Y, Yuan D, Rajkovic A. Germ cell-specific transcriptional regulator sohlh2 is essential for early mouse folliculogenesis and oocyte-specific gene expression. Biol Reprod. 2008;79(6):1176–1182. [PMC free article] [PubMed] [Google Scholar]
58.
Soyal SM, Amleh A, Dean J. FIGalpha, a germ cell-specific transcription factor required for ovarian follicle formation. Development. 2000;127(21):4645–4654. [PubMed] [Google Scholar]
59.
Pangas SA, Choi Y, Ballow DJ, et al. . Oogenesis requires germ cell-specific transcriptional regulators Sohlh1 and Lhx8. Proc Natl Acad Sci U S A. 2006;103(21):8090–8095. [PMC free article] [PubMed] [Google Scholar]
60.
Qin Y, Zhao H, Kovanci E, Simpson JL, Chen ZJ, Rajkovic A. Analysis of LHX8 mutation in premature ovarian failure. Fertil Steril. 2008;89(4):1012–1014. [PMC free article] [PubMed] [Google Scholar]
61.
AlAsiri S, Basit S, Wood-Trageser MA, et al. . Exome sequencing reveals MCM8 mutation underlies ovarian failure and chromosomal instability. J Clin Invest. 2015;125(1):258–262. [PMC free article] [PubMed] [Google Scholar]
62.
Bouali N, Francou B, Bouligand J, et al. . New MCM8 mutation associated with premature ovarian insufficiency and chromosomal instability in a highly consanguineous Tunisian family. Fertil Steril. 2017;108(4):694–702. [PubMed] [Google Scholar]
63.
Wood-Trageser MA, Gurbuz F, Yatsenko SA, et al. . MCM9 mutations are associated with ovarian failure, short stature, and chromosomal instability. Am J Hum Genet. 2014;95(6):754–762. [PMC free article] [PubMed] [Google Scholar]
64.
Desai S, Wood-Trageser M, Matic J, et al. . MCM8 and MCM9 nucleotide variants in women with primary ovarian insufficiency. J Clin Endocrinol Metab. 2017;102(2):576–582. [PMC free article] [PubMed] [Google Scholar]
66.
Colombo R, Pontoglio A, Bini M. A STAG3 missense mutation in two sisters with primary ovarian insufficiency. Eur J Obstet Gynecol Reprod Biol. 2017;216:269–271. [PubMed] [Google Scholar]
67.
He WB, Banerjee S, Meng LL, et al. . Whole-exome sequencing identifies a homozygous donor splice-site mutation in STAG3 that causes primary ovarian insufficiency. Clin Genet. 2018;93(2):340–344. [PubMed] [Google Scholar]
68.
França MM, Nishi MY, Funari MFA, et al. . Two rare loss-of-function variants in the STAG3 gene leading to primary ovarian insufficiency. Eur J Med Genet. 2019;62(3):186–189. [PubMed] [Google Scholar]
69.
Zangen D, Kaufman Y, Zeligson S, et al. . XX ovarian dysgenesis is caused by a PSMC3IP/HOP2 mutation that abolishes coactivation of estrogen-driven transcription. Am J Hum Genet. 2011;89(4):572–579. [PMC free article] [PubMed] [Google Scholar]
70.
Al-Agha AE, Ahmed IA, Nuebel E, et al. . Primary ovarian insufficiency and azoospermia in carriers of a homozygous PSMC3IP stop gain mutation. J Clin Endocrinol Metab. 2018;103(2):555–563. [PMC free article] [PubMed] [Google Scholar]
71.
Yang X, Touraine P, Desai S, et al. . Gene variants identified by whole-exome sequencing in 33 French women with premature ovarian insufficiency. J Assist Reprod Genet. 2019;36(1):39–45. [PMC free article] [PubMed] [Google Scholar]
72.
Wang J, Zhang W, Jiang H, Wu BL; Primary Ovarian Insufficiency Collaboration Mutations in HFM1 in recessive primary ovarian insufficiency. N Engl J Med. 2014;370(10):972–974. [PubMed] [Google Scholar]
73.
Zhe J, Chen S, Chen X, et al. . A novel heterozygous splice-altering mutation in HFM1 may be a cause of premature ovarian insufficiency. J Ovarian Res. 2019;12(1):61. [PMC free article] [PubMed] [Google Scholar]
74.
Weinberg-Shukron A, Renbaum P, Kalifa R, et al. . A mutation in the nucleoporin-107 gene causes XX gonadal dysgenesis. J Clin Invest. 2015;125(11):4295–4304. [PMC free article] [PubMed] [Google Scholar]
75.
Ren Y, Diao F, Katari S, et al. . Functional study of a novel missense single-nucleotide variant of NUP107 in two daughters of Mexican origin with premature ovarian insufficiency. Mol Genet Genomic Med. 2018;6(2):276–281. [PMC free article] [PubMed] [Google Scholar]
76.
Huhtaniemi I, Hovatta O, La Marca A, et al. . Advances in the molecular pathophysiology, genetics, and treatment of primary ovarian insufficiency. Trends Endocrinol Metab. 2018;29(6):400–419. [PubMed] [Google Scholar]
77.
de Vries L, Behar DM, Smirin-Yosef P, Lagovsky I, Tzur S, Basel-Vanagaite L. Exome sequencing reveals SYCE1 mutation associated with autosomal recessive primary ovarian insufficiency. J Clin Endocrinol Metab. 2014;99(10):E2129–E2132. [PubMed] [Google Scholar]
78.
Lee KY, Im JS, Shibata E, et al. . MCM8-9 complex promotes resection of double-strand break ends by MRE11-RAD50-NBS1 complex. Nat Commun. 2015;6:7744. [PMC free article] [PubMed] [Google Scholar]
79.
Lutzmann M, Grey C, Traver S, et al. . MCM8- and MCM9-deficient mice reveal gametogenesis defects and genome instability due to impaired homologous recombination. Mol Cell. 2012;47(4):523–534. [PubMed] [Google Scholar]
80.
Smirin-Yosef P, Zuckerman-Levin N, Tzur S, et al. . A biallelic mutation in the homologous recombination repair gene SPIDR is associated with human gonadal dysgenesis. J Clin Endocrinol Metab. 2017;102(2):681–688. [PubMed] [Google Scholar]
81.
Carlosama C, Elzaiat M, Patiño LC, Mateus HE, Veitia RA, Laissue P. A homozygous donor splice-site mutation in the meiotic gene MSH4 causes primary ovarian insufficiency. Hum Mol Genet. 2017;26(16):3161–3166. [PubMed] [Google Scholar]
83.
Bachelot A, Gilleron J, Meduri G, et al. . A common African variant of human connexin 37 is associated with Caucasian primary ovarian insufficiency and has a deleterious effect in vitro. Int J Mol Med. 2018;41(2):640–648. [PMC free article] [PubMed] [Google Scholar]
84.
Fouquet B, Pawlikowska P, Caburet S, et al. . A homozygous FANCM mutation underlies a familial case of non-syndromic primary ovarian insufficiency. Elife. 2017;6:e30490. [PMC free article] [PubMed] [Google Scholar]
85.
Moriwaki M, Moore B, Mosbruger T, et al. . POLR2C mutations are associated with primary ovarian insufficiency in women. J Endocr Soc. 2017;1(3):162–173. [PMC free article] [PubMed] [Google Scholar]
86.
Chen A, Tiosano D, Guran T, et al. . Mutations in the mitochondrial ribosomal protein MRPS22 lead to primary ovarian insufficiency. Hum Mol Genet. 2018;27(11):1913–1926. [PMC free article] [PubMed] [Google Scholar]
87.
Wang B, Li L, Zhu Y, et al. . Sequence variants of KHDRBS1 as high penetrance susceptibility risks for primary ovarian insufficiency by mis-regulating mRNA alternative splicing. Hum Reprod. 2017;32(10):2138–2146. [PubMed] [Google Scholar]
88.
Zhang D, Liu Y, Zhang Z, et al. . Basonuclin 1 deficiency is a cause of primary ovarian insufficiency. Hum Mol Genet. 2018;27(21):3787–3800. [PubMed] [Google Scholar]
89.
Zhou Y, Qin Y, Qin Y, et al. . Wdr62 is involved in female meiotic initiation via activating JNK signaling and associated with POI in humans. Plos Genet. 2018;14(8):e1007463. [PMC free article] [PubMed] [Google Scholar]
90.
Delcour C, Amazit L, Patino LC, et al. . ATG7 and ATG9A loss-of-function variants trigger autophagy impairment and ovarian failure. Genet Med. 2019;21(4):930–938. [PubMed] [Google Scholar]
91.
Weinberg-Shukron A, Rachmiel M, Renbaum P, et al. . Essential role of BRCA2 in ovarian development and function. N Engl J Med. 2018;379(11):1042–1049. [PMC free article] [PubMed] [Google Scholar]
92.
Turchetti D, Zuntini R, Tricarico R, Bellacosa A. BRCA2 in ovarian development and function. N Engl J Med. 2019;380(11):1086–1087. [PubMed] [Google Scholar]
93.
Franca MM, Han X, Funari MFA, et al. . Exome sequencing reveals the POLR3H gene as a novel cause of primary ovarian insufficiency. J Clin Endocrinol Metab. 2019;104(7):2827–2841. [PMC free article] [PubMed] [Google Scholar]
94.
Patiño LC, Beau I, Morel A, et al. . Functional evidence implicating NOTCH2 missense mutations in primary ovarian insufficiency etiology. Hum Mutat. 2019;40(1):25–30. [PubMed] [Google Scholar]
95.
Tucker EJ, Grover SR, Robevska G, van den Bergen J, Hanna C, Sinclair AH. Identification of variants in pleiotropic genes causing “isolated” premature ovarian insufficiency: implications for medical practice. Eur J Hum Genet. 2018;26(9):1319–1328. [PMC free article] [PubMed] [Google Scholar]
96.
Chapman C, Cree L, Shelling AN. The genetics of premature ovarian failure: current perspectives. Int J Womens Health. 2015;7:799–810. [PMC free article] [PubMed] [Google Scholar]
97.
Simon AM, Goodenough DA, Li E, Paul DL. Female infertility in mice lacking connexin 37. Nature. 1997;385(6616):525–529. [PubMed] [Google Scholar]
98.
Bianchi E, Barbagallo F, Valeri C, et al. . Ablation of the Sam68 gene impairs female fertility and gonadotropin-dependent follicle development. Hum Mol Genet. 2010;19(24):4886–4894. [PubMed] [Google Scholar]
99.
Carlosama C, Patiño LC, Beau I, et al. . A novel mutation in KHDRBS1 in a patient affected by primary ovarian insufficiency. Clin. Endocrinol. 2018;89(2):245–246. [PubMed] [Google Scholar]
100.
Dikic I, Elazar Z. Mechanism and medical implications of mammalian autophagy. Nat Rev Mol Cell Biol. 2018;19(6):349–364. [PubMed] [Google Scholar]
101.
Komatsu M, Waguri S, Chiba T, et al. . Loss of autophagy in the central nervous system causes neurodegeneration in mice. Nature. 2006;441(7095):880–884. [PubMed] [Google Scholar]
102.
Song ZH, Yu HY, Wang P, et al. . Germ cell-specific Atg7 knockout results in primary ovarian insufficiency in female mice. Cell Death Dis. 2015;6:e1589. [PMC free article] [PubMed] [Google Scholar]
103.
Wang H, Wan H, Li X, et al. . Atg7 is required for acrosome biogenesis during spermatogenesis in mice. Cell Res. 2014;24(7):852–869. [PMC free article] [PubMed] [Google Scholar]
104.
Yamaguchi J, Suzuki C, Nanao T, et al. . Atg9a deficiency causes axon-specific lesions including neuronal circuit dysgenesis. Autophagy. 2018;14(5):764–777. [PMC free article] [PubMed] [Google Scholar]
105.
White RJ. RNA polymerases I and III, growth control and cancer. Nat Rev Mol Cell Biol. 2005;6(1):69–78. [PubMed] [Google Scholar]
106.
Bernard G, Chouery E, Putorti ML, et al. . Mutations of POLR3A encoding a catalytic subunit of RNA polymerase Pol III cause a recessive hypomyelinating leukodystrophy. Am J Hum Genet. 2011;89(3):415–423. [PMC free article] [PubMed] [Google Scholar]
107.
Saitsu H, Osaka H, Sasaki M, et al. . Mutations in POLR3A and POLR3B encoding RNA Polymerase III subunits cause an autosomal-recessive hypomyelinating leukoencephalopathy. Am J Hum Genet. 2011;89(5):644–651. [PMC free article] [PubMed] [Google Scholar]
108.
Tétreault M, Choquet K, Orcesi S, et al. . Recessive mutations in POLR3B, encoding the second largest subunit of Pol III, cause a rare hypomyelinating leukodystrophy. Am J Hum Genet. 2011;89(5):652–655. [PMC free article] [PubMed] [Google Scholar]
109.
Richards MR, Plummer L, Chan YM, et al. . Phenotypic spectrum of POLR3B mutations: isolated hypogonadotropic hypogonadism without neurological or dental anomalies. J Med Genet. 2017;54(1):19–25. [PMC free article] [PubMed] [Google Scholar]
110.
Dumortier A, Wilson A, MacDonald HR, Radtke F. Paradigms of notch signaling in mammals. Int J Hematol. 2005;82(4):277–284. [PubMed] [Google Scholar]
111.
Trombly DJ, Woodruff TK, Mayo KE. Suppression of Notch signaling in the neonatal mouse ovary decreases primordial follicle formation. Endocrinology. 2009;150(2):1014–1024. [PMC free article] [PubMed] [Google Scholar]
112.
Wan L, Han J, Liu T, et al. . Scaffolding protein SPIDR/KIAA0146 connects the Bloom syndrome helicase with homologous recombination repair. Proc Natl Acad Sci U S A. 2013;110(26):10646–10651. [PMC free article] [PubMed] [Google Scholar]
113.
Kneitz B, Cohen PE, Avdievich E, et al. . MutS homolog 4 localization to meiotic chromosomes is required for chromosome pairing during meiosis in male and female mice. Genes Dev. 2000;14(9):1085–1097. [PMC free article] [PubMed] [Google Scholar]
114.
de Vries SS, Baart EB, Dekker M, et al. . Mouse MutS-like protein Msh5 is required for proper chromosome synapsis in male and female meiosis. Genes Dev. 1999;13(5):523–531. [PMC free article] [PubMed] [Google Scholar]
115.
Bogliolo M, Surrallés J. Fanconi anemia: a model disease for studies on human genetics and advanced therapeutics. Curr Opin Genet Dev. 2015;33:32–40. [PubMed] [Google Scholar]
116.
Kasak L, Punab M, Nagirnaja L, et al. ; GEMINI Consortium Bi-allelic recessive loss-of-function variants in FANCM cause non-obstructive azoospermia. Am J Hum Genet. 2018;103(2):200–212. [PMC free article] [PubMed] [Google Scholar]
117.
Ma J, Zeng F, Schultz RM, Tseng H. Basonuclin: a novel mammalian maternal-effect gene. Development. 2006;133(10):2053–2062. [PubMed] [Google Scholar]
118.
Wasserman T, Katsenelson K, Daniliuc S, Hasin T, Choder M, Aronheim A. A novel c-Jun N-terminal kinase (JNK)-binding protein WDR62 is recruited to stress granules and mediates a nonclassical JNK activation. Mol Biol Cell. 2010;21(1):117–130. [PMC free article] [PubMed] [Google Scholar]
119.
Bilgüvar K, Oztürk AK, Louvi A, et al. . Whole-exome sequencing identifies recessive WDR62 mutations in severe brain malformations. Nature. 2010;467(7312):207–210. [PMC free article] [PubMed] [Google Scholar]
120.
Sgourdou P, Mishra-Gorur K, Saotome I, et al. . Disruptions in asymmetric centrosome inheritance and WDR62-Aurora kinase B interactions in primary microcephaly. Sci Rep. 2017;7:43708. [PMC free article] [PubMed] [Google Scholar]
121.
Xia F, Taghian DG, DeFrank JS, et al. . Deficiency of human BRCA2 leads to impaired homologous recombination but maintains normal nonhomologous end joining. Proc Natl Acad Sci U S A. 2001;98(15):8644–8649. [PMC free article] [PubMed] [Google Scholar]
122.
Davies AA, Masson JY, McIlwraith MJ, et al. . Role of BRCA2 in control of the RAD51 recombination and DNA repair protein. Mol Cell. 2001;7(2):273–282. [PubMed] [Google Scholar]
123.
Daum H, Peretz T, Laufer N. BRCA mutations and reproduction. Fertil Steril. 2018;109(1):33–38. [PubMed] [Google Scholar]
124.
Levine AJ, Tomasini R, McKeon FD, Mak TW, Melino G. The p53 family: guardians of maternal reproduction. Nat Rev Mol Cell Biol. 2011;12(4):259–265. [PubMed] [Google Scholar]
125.
Flores ER, Tsai KY, Crowley D, et al. . p63 and p73 are required for p53-dependent apoptosis in response to DNA damage. Nature. 2002;416(6880):560–564. [PubMed] [Google Scholar]
126.
Suh EK, Yang A, Kettenbach A, et al. . p63 protects the female germ line during meiotic arrest. Nature. 2006;444(7119):624–628. [PubMed] [Google Scholar]
127. Dumay-Odelot H, Durrieu-Gaillard S, Da Silva D, Roeder RG, Teichmann M. Cell growth- and differentiation-dependent regulation of RNA polymerase III transcription. Cell Cycle. 2010;9(18):3687–3699. [PMC free article] [PubMed] [Google Scholar]
128.
Pierce SB, Chisholm KM, Lynch ED, et al. . Mutations in mitochondrial histidyl tRNA synthetase HARS2 cause ovarian dysgenesis and sensorineural hearing loss of Perrault syndrome. Proc Natl Acad Sci U S A. 2011;108(16):6543–6548. [PMC free article] [PubMed] [Google Scholar]
129.
Pierce SB, Gersak K, Michaelson-Cohen R, et al. . Mutations in LARS2, encoding mitochondrial leucyl-tRNA synthetase, lead to premature ovarian failure and hearing loss in Perrault syndrome. Am J Hum Genet. 2013;92(4):614–620. [PMC free article] [PubMed] [Google Scholar]
(責(zé)任編輯：佳學(xué)基因)
