【卵巢早衰 基因檢測(cè)】基因解碼讓女性魅力常在

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(jiǎn)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(gè)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(bào)告了先進(jìn)例原發(fā)性卵巢功能不全。佳學(xué)基因發(fā)現(xiàn)，對(duì)于這種疾病的描術(shù)，使用了不同的名稱。在國(guó)際上也是如此。歐洲人類生殖和胚胎學(xué)學(xué)會(huì)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(guó)婦產(chǎn)科學(xué)會(huì)（ACOG）委員會(huì)則支持“原發(fā)性卵巢功能不全”。美國(guó)國(guó)立衛(wèi)生研究院堅(jiān)持認(rèn)為這一術(shù)語是恰當(dāng)?shù)模驗(yàn)橛行㏄OI患者可能會(huì)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(gè)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(chǎng)景，選擇使用不同的表述方法，目的是為了更好的傳遞知識(shí)。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(shí)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(shí)。通過對(duì)675名女性原發(fā)性卵巢早衰進(jìn)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(diǎn)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(duì)74名卵巢早衰所做的研究中，評(píng)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?yàn)樵l(fā)性閉經(jīng)主要在內(nèi)分泌科進(jìn)行評(píng)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(zhǎng)而增加（20歲時(shí)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(guó)的7個(gè)地點(diǎn)對(duì)40-55歲的婦女進(jìn)行了橫斷面調(diào)查（全國(guó)婦女研究[SWAN]），確定了11652名婦女中自我報(bào)告的POI患病率，沒有明顯的種族區(qū)別。事實(shí)上，有1.1%的女性患有POI，其中1.0%是白人，1.4%是非裔美國(guó)人，1.4%是西班牙裔，0.5%是中國(guó)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(guó)和歐洲指南，POI診斷是通過連續(xù)兩次測(cè)量促性腺激素水平，兩次之間的間隔至少1個(gè)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(gè)月。

POI診斷確認(rèn)后，應(yīng)進(jìn)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(píng)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(cè)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(cè)未能找到病因的卵巢早衰患者可能會(huì)由于找到病因而得到更有針對(duì)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(jìn)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(shí)，基因解碼也揭示，多個(gè)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(cè)進(jìn)行得更為全面和有效。據(jù)透露，佳學(xué)基因等機(jī)構(gòu)正在著力研究不同基因?qū)е碌穆殉苍缢サ尼槍?duì)性調(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(gè)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(duì)核型進(jìn)行數(shù)值變化的評(píng)估，基因解碼倡導(dǎo)的全外顯子測(cè)序方法賊近已成為評(píng)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(kuò)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(duì)于動(dòng)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(dòng)態(tài)突變，因?yàn)榇蠹s20%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(diǎn)中斷的基因或X染色體點(diǎn)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(shí)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(cè)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?yàn)樗鼈冊(cè)诎l(fā)育和/或卵巢功能中的作用。它們?cè)诠δ苌峡煞譃榕c（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(hào)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?yàn)榈蛲鲞^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(shí)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(gè)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(huì)出現(xiàn)綜合征或孤立的卵巢早衰表型。此外，生長(zhǎng)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(jìn)卵巢生長(zhǎng)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(duì)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(jí)卵泡階段的阻塞而不育。這與之前觀察到的雜合子錯(cuò)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(dòng)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(huì)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(gè)純合變異的家族病例；一名中國(guó)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?cè)趦蓚€(gè)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(huì)促進(jìn)人類和小鼠的卵巢功能衰竭。

減數(shù)分裂和DNA修復(fù)基因?；蚪獯a普遍采用高通量測(cè)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(jìn)階段，在胎兒期停留在先進(jìn)階段，當(dāng)婦女進(jìn)入青春期時(shí)重新開始細(xì)胞分裂；次級(jí)卵母細(xì)胞在排卵時(shí)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(duì)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(jìn)了小鼠減數(shù)分裂過程中的錯(cuò)誤，例如MCM8-/-小鼠的減數(shù)分裂前期I停止、初級(jí)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(cè)序?yàn)榛A(chǔ)條件的基因解碼分析方法不斷被鑒定明確下來。

B-2號(hào)?；蚪獯a揭示的新基因

此外，在人類和動(dòng)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(gè)。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(jìn)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(hào)傳導(dǎo)，影響卵泡發(fā)育。Patiño及其合作者報(bào)告了體外證據(jù)，證明BMPR2中的p.Ser987Phe突變?cè)黾恿藘?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(cuò)義變體（c.946G>A:p.Gly316Ser）。雖然這種突變?cè)诎追N人的對(duì)照組中還沒有報(bào)道，但在非洲個(gè)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(jī)制可能涉及縫隙連接內(nèi)吞和溶酶體降解的增加。事實(shí)上，在這個(gè)法國(guó)隊(duì)列中進(jìn)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(hào)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(jìn)次懷孕延遲、產(chǎn)仔量少、卵巢中次級(jí)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(cè)序（WES），在一名中國(guó)母親和一名患POI的大女兒中發(fā)現(xiàn)了一個(gè)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(gè)單等位基因突變（c.263C>T:p.Pro88Leu）。體外試驗(yàn)表明KHDRBS1突變（c.460A>G）對(duì)選擇性剪接的影響；然而，還沒有進(jìn)行體內(nèi)研究[98]。KHDRBS1的另一個(gè)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(jìn)一步的功能研究來驗(yàn)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(duì)不同形式的應(yīng)激反應(yīng)中，如營(yíng)養(yǎng)缺乏、生長(zhǎng)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(duì)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(huì)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(jī)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(jìn)了雌性小鼠的亞生育能力[102]。在雄性小鼠中，Atg7的破壞會(huì)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(jìn)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(gè)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(zhǎng)、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(yíng)養(yǎng)不良綜合征）相關(guān)，但在人類疾病的情況下，尚未報(bào)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(bào)道了兩個(gè)POI不相關(guān)家系中POLR3H中的一個(gè)新的雙等位基因錯(cuò)義突變（c.149A>G:p.Asp50Gly），并用CRISPR/Cas9方法生成了兩個(gè)小鼠系，以評(píng)估POLR3H-p.Asp50Gly突變的內(nèi)在機(jī)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(diǎn)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(shí)間或懷孕時(shí)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(jí)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(jìn)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(yùn)決定和分化過程[110]。相關(guān)的蛋白質(zhì)，包括四個(gè)NOTCH受體（NOTCH 1-4）和5個(gè)NOTCH配體（鋸齒狀1-2和DELTA-LIKE 1、3和4），與無脊椎動(dòng)物（果蠅、秀麗隱桿線蟲）和哺乳動(dòng)物自我更新系統(tǒng)的穩(wěn)態(tài)維持有關(guān)[110]。NOTCH信號(hào)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(shí)[111]。在NOTCH信號(hào)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(zhǎng)骨彎曲和脊椎畸形（MIM-102500）。

賊近報(bào)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(gè)患者都攜帶一個(gè)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(gè)NOTCH2突變（p.Ser1804Leu、p.Ala2316Val和p.Pro2359Ala）的轉(zhuǎn)錄活性已經(jīng)得到證實(shí)，盡管在對(duì)照組和具有所有所述突變體的個(gè)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(jī)制的蛋白質(zhì)。SPIDR的缺失促進(jìn)了姐妹染色單體缺陷、基因組不穩(wěn)定性和對(duì)DNA損傷效應(yīng)的敏感性的增加[112]。在2個(gè)有POI的姐妹中發(fā)現(xiàn)了一個(gè)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(duì)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(zhǎng)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(jī)制。診斷為繼發(fā)性閉經(jīng)的兩個(gè)姐妹被發(fā)現(xiàn)在MSH4中存在純合供體剪接位點(diǎn)突變（c.2355+1G>a:p.Ile743_Lys785del）[81]。在一個(gè)中國(guó)隊(duì)列中，在2個(gè)分離的POI姐妹中發(fā)現(xiàn)了一個(gè)新的MSH5純合子錯(cuò)義突變（c.1459G>T:p.Asp487Tyr）。在一項(xiàng)體外研究中，使用敲除小鼠（Msh5D486Y/D486Y）進(jìn)行的功能評(píng)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(bǔ)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?cè)谠摷膊≈衅鹬匾饔肹115]。然而，在兩個(gè)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(duì)姐妹的淋巴細(xì)胞分析顯示，染色體斷裂和對(duì)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(hào)（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(shí)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(duì)一個(gè)有7例POI感染婦女的中國(guó)家庭進(jìn)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(cuò)義變體（c.1595T>c:p.Leu532Pro）[88]。在體外和體內(nèi)實(shí)驗(yàn)中證實(shí)了BNC1半抗原的不足。有缺失和錯(cuò)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(chǔ)備減少（即FSH升高、卵巢大小減小和卵泡大小減?。┒憩F(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(cuò)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(píng)估了兩例診斷為原發(fā)性閉經(jīng)的散發(fā)性POI病例，每個(gè)病例都有一個(gè)錯(cuò)義突變（c.1796G>A:p.Cys599Tyr）或一個(gè)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(gè)與女性不育相關(guān)的不同基因（BRCA2和SPTB）中也有3個(gè)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(hào)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(duì)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?cè)黾恿私K生癌癥的風(fēng)險(xiǎn)；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(gè)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(gè)姐妹的急性髓細(xì)胞白血病長(zhǎng)期緩解[91]。這些兄弟姐妹攜帶BRCA2的復(fù)合雜合子截?cái)嗤蛔儯s7579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(gè)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(jìn)入雙鏈DNA斷裂，表明對(duì)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?；蚰[瘤。另外，2個(gè)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(gè)變體（c.[6468_6469delTC]；[c.8471G>c]）在兩個(gè)兄弟姐妹中都被發(fā)現(xiàn)，隨后通過長(zhǎng)程PCR證實(shí)為反式[92]。雖然賊后2例可能擴(kuò)大了BRCA2表型的范圍，但其致病性需要進(jìn)一步的功能驗(yàn)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(jí)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(duì)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(gè)器官的復(fù)雜綜合征有關(guān)；然而，賊近在一個(gè)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(gè)單等位基因無意義致病性變體（c.1794G>A:p.Arg594*）。需要進(jìn)一步的功能研究來評(píng)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(xiàng)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(gè)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(gè)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(bào)告有理由證實(shí)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(gè)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(qiáng)大的遺傳背景和低成本、高通量的并行測(cè)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。

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【卵巢早衰基因檢測(cè)】基因解碼讓女性魅力常在