王心緣，孫睿，高原青

綜 述

Prader-Willi綜合征下丘腦功能障礙的遺傳機制研究進展

王心緣，孫睿，高原青

南京醫(yī)科大學(xué)藥學(xué)院，江蘇省心腦血管藥物重點實驗室，南京 211166

Prader-Willi 綜合征(Prader-Willi syndrome, PWS)是一種罕見的先天發(fā)育性疾病，主要由父系15號染色體長臂15q11～q13區(qū)域基因缺失或沉默引起。PWS臨床表型復(fù)雜，主要包括無法滿足的饑餓、病態(tài)的肥胖、智力發(fā)育遲緩、性腺發(fā)育不良等，多數(shù)癥狀提示與下丘腦的功能障礙相關(guān)。然而到目前為止，PWS的分子遺傳機制尚不明確，尤其是基因和臨床表現(xiàn)之間的對應(yīng)關(guān)系和詳細(xì)機制有待進一步研究。本文以PWS“基因型–下丘腦功能障礙表型”之間的關(guān)聯(lián)為重點，綜述了15q11～q13區(qū)域基因(、、、、、、和等)與PWS患者過度攝食和肥胖、性腺發(fā)育不良、睡眠呼吸障礙、生長發(fā)育遲緩等表型相關(guān)的研究進展，旨在加深對PWS遺傳機制的理解，探討潛在的PWS藥物靶點的可能性。

Prader-Willi 綜合征；下丘腦；遺傳機制

Prader-Willi綜合征(Prader-Willi syndrome, PWS)又稱小胖–威利綜合征，是一種罕見的、多系統(tǒng)的神經(jīng)發(fā)育性疾病。1956年，Prader等[1]根據(jù)特有的臨床表型首次報道了9名具有該疾病特征的患者。65%～75%的典型PWS患者與父系15q11～q13區(qū)域基因缺失有關(guān)，20%～30%具有母系同源二倍體，1%～ 3%的不典型PWS患者由15號染色體重排或印記缺陷引起[2]。PWS每年的發(fā)病率約為1/10,000～1/30,000，目前尚沒有辦法根治，只能對癥治療，且終身需要照料和監(jiān)管，給患者和家庭帶來極大的負(fù)擔(dān)。由于PWS的很多臨床特征與其他代謝和發(fā)育疾病有重合，根據(jù)臨床表現(xiàn)對PWS做出早期診斷比較困難，容易出現(xiàn)兒童期漏診以及成年期肥胖患者誤診，因此對可疑病患進行基因檢測是目前PWS診斷的重要手段[3]。

PWS臨床表型復(fù)雜，從胎兒到成年期表現(xiàn)出不同癥狀。胎兒期胎動減少，多發(fā)生早產(chǎn)或難產(chǎn)；新生兒期出現(xiàn)肌張力低下、吸吮無力、喂養(yǎng)困難、生長緩慢、外生殖器發(fā)育不良等；兒童期一般表現(xiàn)為身材矮小、近視、膚色較淺、齲齒、智力障礙和行為問題，一般自8歲起開始出現(xiàn)無節(jié)制飲食并導(dǎo)致超重或肥胖；青春期和成年期肥胖體型會更加明顯，伴隨由于肥胖所引起的一系列并發(fā)癥，以及性腺發(fā)育不良、骨質(zhì)疏松、脊柱側(cè)凸、嗜睡和抑郁等癥狀[4,5]。下丘腦是人體基礎(chǔ)代謝功能的調(diào)控中心。PWS的許多表型與下丘腦功能障礙密切相關(guān)，如體重和攝食異常、體溫調(diào)節(jié)異常、性腺發(fā)育不良、內(nèi)分泌功能紊亂等[6～10]，由過度攝食所引起的肥胖及其并發(fā)癥也是造成PWS患者死亡的重要因素[11]。然而，PWS下丘腦功能障礙與缺失區(qū)域基因的功能之間的關(guān)系尚未被完全闡明。本文主要對下丘腦功能障礙相關(guān)的遺傳證據(jù)及其研究進展展開了綜述，以期為PWS的診斷和治療提供借鑒和參考。

1 PWS下丘腦功能障礙表型

1.1 過度攝食和肥胖

Miller等[12]將PWS患者病程分為7個不同的營養(yǎng)階段。在新生兒早期和嬰兒期，PWS患者主要表現(xiàn)為肌張力低下、吸吮不良、喂養(yǎng)困難，容易出現(xiàn)生長遲緩或停滯，甚至可能死亡。在2～4歲時，PWS患者食欲和正常兒童無明顯區(qū)別，體重開始增長；4～8歲時，食欲和體重異常增加，一般自8歲起，PWS患者開始出現(xiàn)持續(xù)的食欲亢進，缺乏正常的飽腹感。在這個階段通常需要一對一的監(jiān)督管理，以防止由于暴飲暴食導(dǎo)致的胃破裂、胃壞死和窒息死亡[13]。食欲亢進、過度攝食常常導(dǎo)致PWS患者出現(xiàn)早發(fā)性病態(tài)肥胖和相關(guān)并發(fā)癥，這是PWS死亡的常見原因[14]。目前對PWS患者嬰幼兒期喂養(yǎng)不良、兒童期開始出現(xiàn)過度攝食和肥胖的病理機制仍不清楚。早期的飲食治療和長期的營養(yǎng)監(jiān)測可以改善PWS患者的預(yù)后，包括嬰幼兒期通過輔助喂養(yǎng)保證足夠的能量攝入，通過身體活動和飲食管理預(yù)防PWS肥胖等，至今尚沒有藥物可以幫助控制食欲。減重手術(shù)曾被認(rèn)為是重要的對癥治療方案，但是關(guān)于手術(shù)的有效性存在較大爭議，并且手術(shù)無法改善患者的飽腹感缺失和過度攝食行為，所以目前尚不推薦該手術(shù)用于常規(guī)治療[15,16]。

1.2 性腺功能減退

性腺功能減退通常被認(rèn)為是下丘腦功能障礙和原發(fā)性性腺功能低下共同導(dǎo)致的。大多數(shù)患者從新生兒期開始出現(xiàn)并伴隨一生，表現(xiàn)為外生殖器發(fā)育不良。在男性中最典型的表現(xiàn)是陰囊發(fā)育不良，陰囊較小，單側(cè)或雙側(cè)隱睪癥見于80%～90%的男性患者[17]，女性主要表現(xiàn)為陰唇陰蒂發(fā)育不全[9]；青春期PWS患者通常出現(xiàn)青春期發(fā)育不完全、青春期發(fā)育延遲，有極少數(shù)PWS病例會伴有中樞性早熟；成年期PWS患者多表現(xiàn)為不孕不育、原發(fā)性閉經(jīng)、月經(jīng)稀疏等。PWS男性隱睪和外生殖器發(fā)育不良患者，在出生后早期注射睪酮或人絨毛膜促性腺激素可以改善陰莖大小、促進陰囊發(fā)育、協(xié)助調(diào)整睪丸位置下降到陰囊等，近端型隱睪和遠(yuǎn)端型隱睪人絨毛膜促性腺激素療效不佳者可以考慮外科手術(shù)治療[18,19]。對于PWS患者性激素替代治療以誘導(dǎo)或促進青春期發(fā)育目前尚無統(tǒng)一的共識，且替代治療藥物通常價格昂貴，用藥依從性和副作用問題較大，需要充分考慮利弊并積極探索更優(yōu)化的治療方案。

1.3 睡眠呼吸障礙

PWS患者表現(xiàn)為明顯的晝夜節(jié)律失調(diào)性睡眠障礙、睡眠中斷和睡眠呼吸障礙。有研究表明睡眠呼吸障礙還與神經(jīng)認(rèn)知功能的顯著缺陷有關(guān)，包括PWS患者的注意力不集中、白天過度嗜睡和易激惹等表現(xiàn)[20]。許多PWS患者患有阻塞性、中樞性和混合性睡眠呼吸暫停綜合征。肥胖、肌張力低下、氣道狹窄、脊柱側(cè)彎等被列為影響PWS睡眠呼吸障礙嚴(yán)重程度的重要因素[21]。下丘腦是睡眠覺醒和晝夜節(jié)律的重要調(diào)控中樞，多項研究也表明，PWS患者睡眠呼吸障礙與下丘腦功能失調(diào)相關(guān)，如下丘腦食欲素神經(jīng)元總數(shù)和編碼食欲素前體的基因表達(dá)水平發(fā)生了顯著變化，食欲素系統(tǒng)與睡眠障礙和認(rèn)知功能密切相關(guān)[22,23]。興奮劑藥物(莫達(dá)非尼、哌醋甲酯或苯丙胺鹽混合物)已被證明可改善發(fā)作性睡病患者的日間過度嗜睡[24]。對PWS引起的呼吸障礙，目前多為手術(shù)治療，如腺扁桃體切除術(shù)聯(lián)合持續(xù)氣道正壓通氣等[25]。

1.4 生長發(fā)育遲緩

40%～100%的PWS患兒因生長激素缺乏導(dǎo)致身材矮小，一般自嬰兒時期即會出現(xiàn)[5]。兒童時期表現(xiàn)為小手和小腳，語言和運動系統(tǒng)也較同齡人發(fā)育緩慢；學(xué)齡期表現(xiàn)出嚴(yán)重的學(xué)習(xí)困難，伴有一系列的行為問題，如易怒、固執(zhí)、脾氣暴躁等[4,26]。到其青春期和成年期，PWS患者身高明顯低于正常水平，還常伴有脊柱側(cè)彎、骨質(zhì)疏松等多系統(tǒng)受累癥狀[27]。有研究指出，PWS患者在童年時期接受生長激素治療后，能夠達(dá)到正常的成年身高，還可以減緩PWS患者行為問題的發(fā)展[28]。重組人生長激素于2000年得到美國食品藥品監(jiān)督管理局批準(zhǔn)，用于治療PWS患者的生長發(fā)育障礙[29]。

2 PWS基因型和表型的關(guān)系

典型的PWS綜合征患者是與父系15號染色體長臂區(qū)域基因缺失有關(guān)。到目前為止，尚未發(fā)現(xiàn)有單一的基因突變可以導(dǎo)致這種遺傳性疾病的所有表型。染色體15q11～q13區(qū)域由著絲粒至端粒方向可分為四組基因：(1)位于BP1～BP2斷點之間的近端非印跡區(qū)域，包含4個雙親同等表達(dá)基因：、、、；(2) PWS僅父系表達(dá)印記區(qū)域：包含五個蛋白質(zhì)編碼基因(、、、、)、一個基因簇和幾個反義轉(zhuǎn)錄本；(3)含有母系優(yōu)先表達(dá)基因的Angelman綜合征區(qū)域：和；(4)遠(yuǎn)端非印記區(qū)域：包含3個受體亞基、和[30]。根據(jù)缺失區(qū)域的不同PWS又可分為I型和II型，包含BP2～BP3區(qū)域基因缺失的為II型，I型相比于II型額外缺失了BP1～BP2非印記區(qū)域[31](圖1)。研究發(fā)現(xiàn)，I型PWS患者與II型相比，具有更嚴(yán)重的智力障礙和行為問題[32,33]，很有可能是由于額外缺失的非印記區(qū)基因所引起的。本文將詳細(xì)總結(jié)染色體15q11～q13區(qū)域中與下丘腦功能障礙密切相關(guān)的基因的研究進展。

圖1 15q11～q13區(qū)域基因表達(dá)示意圖

2.1 近端非印記區(qū)缺失

15號染色體近端非印記區(qū)包含4個在父系和母系等位基因中同等表達(dá)的基因，PWS患者表現(xiàn)為父系染色體上的基因缺失。只包含這4個非印記區(qū)基因缺失的疾病被稱為15q11.2 BP1～BP2微缺失綜合征[34]，Butler等[35]報告了200多例15q11.2 BP1～BP2微缺失患者，多表現(xiàn)為發(fā)育遲緩、語言障礙、運動功能減退和自閉癥譜系障礙等。

2.1.1

()基因編碼鎂離子轉(zhuǎn)運蛋白，在大腦中表達(dá)量最高。Chang等[36]發(fā)現(xiàn)15q11.2 BP1～BP2微重復(fù)與神經(jīng)性厭食癥密切相關(guān)，介導(dǎo)的鎂離子轉(zhuǎn)運失調(diào)是其中的重要機制，由此猜測，的父系缺失可能與PWS患者食欲亢進、過度攝食相關(guān)，而嬰兒期喂養(yǎng)困難、吸吮無力可能是其他基因缺失的結(jié)果。Chen等[37]的報告則表明，PWS患者的下丘腦神經(jīng)分泌顆粒和神經(jīng)肽的產(chǎn)生減少，雖然作者將這種減少解釋為的缺失，但NIPA1蛋白與內(nèi)體的共定位表明其也與分泌途徑相關(guān)，可能與協(xié)同作用，缺失會阻礙神經(jīng)元的成熟和分泌，影響到下丘腦功能[38]。

2.1.2

在結(jié)構(gòu)和功能上與類似，編碼鎂離子轉(zhuǎn)運蛋白，定位于內(nèi)體、神經(jīng)元和內(nèi)皮細(xì)胞表面質(zhì)膜上[39]。基因突變可以引起兒童癲癇，與大腦發(fā)育遲緩、神經(jīng)精神異常等表型密切相關(guān)。神經(jīng)元興奮性由各種受體和離子通道調(diào)節(jié)，編碼鎂離子轉(zhuǎn)運蛋白，其缺失會降低大電導(dǎo)鉀離子通道電流，增強神經(jīng)元的興奮性，影響神經(jīng)元的穩(wěn)態(tài)和功能，進而影響到大腦發(fā)育和精神狀況[40]。在小鼠和2型糖尿病骨質(zhì)疏松癥的體外模型中，也觀察到表達(dá)降低，可能通過調(diào)節(jié)線粒體自噬途徑在2型糖尿病中積極調(diào)節(jié)成骨細(xì)胞的成骨能力[41]，這與PWS患者青春期及成年期過度肥胖常伴隨糖尿病和骨質(zhì)疏松等表型一致。此外，小鼠骨質(zhì)疏松癥的機制復(fù)雜，不能排除瘦素信號在其中所起的作用。瘦素與位于下丘腦的瘦素受體結(jié)合，通過中樞途徑調(diào)控骨骼形成和攝食環(huán)路，而表達(dá)降低很有可能影響瘦素系統(tǒng)功能，進而影響到下丘腦對成骨過程的調(diào)控[42]。

2.1.3

()是γ-微管蛋白復(fù)合物的核心成分，是中心體微管成核所必需的[43]?；蛲蛔兣c原發(fā)性小頭癥和神經(jīng)發(fā)育遲緩相關(guān)[44]。Wolf等[45]通過基因組分析認(rèn)為對神經(jīng)精神疾病患者的強迫行為有貢獻(xiàn)，可能與PWS患者強迫性攝食和行為問題相關(guān)。TUBGCP5蛋白在心臟，骨骼肌和大腦中表達(dá)最高，參與細(xì)胞分裂的關(guān)鍵過程，但與PWS患者相關(guān)的下丘腦功能障礙表型的具體機制仍有待進一步研究。

2.1.4

()參與調(diào)節(jié)細(xì)胞骨架動力學(xué)和蛋白質(zhì)翻譯。早期的研究表明，具有PWS樣癥狀的脆性X染色體綜合征患者的mRNA表達(dá)水平通常降低了兩到四倍，提示表達(dá)的降低可能與更嚴(yán)重的神經(jīng)發(fā)育障礙相關(guān)[46]。近期的一項研究表明，單倍體不足小鼠表現(xiàn)出強迫性行為和飲食紊亂[47]。

CYFIP1在細(xì)胞內(nèi)是WAVE復(fù)合體(Wiskott- Aldrich syndrome protein-family Verprolin homologous protein, WAVE)的組成蛋白之一。WAVE復(fù)合體本身對其下游的肌動蛋白成核因子(Actin-related protein 2/3 complex, Arp2/3)無直接活性，但可以通過CYFIP1轉(zhuǎn)導(dǎo)Rac信號，誘導(dǎo)WAVE復(fù)合體構(gòu)象發(fā)生變化，觸發(fā)Arp2/3成核，調(diào)控肌動蛋白和細(xì)胞骨架[48]。單倍體不足小鼠表現(xiàn)出突觸功能障礙、肌動蛋白聚合異常，可能因此影響到神經(jīng)元穩(wěn)態(tài)和功能[49]。此外，有研究表明，髓鞘形成的早期階段少突膠質(zhì)細(xì)胞的成熟和髓鞘包裹的啟動需要Arp2/3組裝肌動蛋白[50]，而的缺失很有可能影響髓鞘生發(fā)和動作電位的快速傳播，進而影響學(xué)習(xí)記憶等行為，與PWS生長發(fā)育遲緩、智力障礙表型密切相關(guān)。

CYFIP1還可以與脆性X智力低下蛋白(Fragile X mental retardation protein, FMRP)和翻譯起始因4E (eukaryotic translation initiation factor 4E, eIF4E)相互作用[51]。eIF4E是帽結(jié)合蛋白，與解旋酶eIF4A和支架蛋白eIF4G等蛋白質(zhì)協(xié)同作用，與mRNA結(jié)合，調(diào)控核糖體募集和翻譯起始，CYFIP1-eIF4E- FMR1復(fù)合物的活性調(diào)控蛋白質(zhì)翻譯過程[52]。Conn等[53]的研究指出調(diào)控eIF4E可以抑制高脂食物引起的肥胖癥和脂肪肝，由此推測的缺失很有可能引起eIF4E過表達(dá)，進而引起PWS患者食欲亢進和病態(tài)肥胖。

2.2 PWS僅父系表達(dá)印記區(qū)缺失

2.2.1

()是第一個對促性腺激素釋放激素(Gonadotropin-releasing hor-mone, GnRH)分泌具有抑制作用的基因[54]。缺失患者表現(xiàn)為中樞性早熟的典型特征[55]。與蛋白質(zhì)泛素化有關(guān)，發(fā)揮著信號轉(zhuǎn)導(dǎo)、細(xì)胞周期調(diào)控、細(xì)胞分化等作用。在嬰兒期和幼年期下丘腦弓狀核kisspeptin神經(jīng)元中高度表達(dá)，很可能通過泛素化修飾調(diào)控kisspeptin和速激肽3的啟動子活性，抑制GnRH的分泌。在青春期開始前表達(dá)減少，減少對GnRH分泌的抑制，調(diào)控青春期的發(fā)育[56]。然而，中樞性早熟在PWS患者中較為罕見[57]。Ludwig等[58]曾報道過一例用促性腺激素釋放激素類似物和重組人生長激素聯(lián)合治療罕見的中樞性早熟PWS患者，證明促性腺激素釋放激素類似物對這種特殊的PWS患者青春期發(fā)育狀況有益。

典型的PWS患者以外生殖器發(fā)育不良和低促性腺激素、性腺功能減退為特征。的缺失與典型PWS患者性腺發(fā)育不良、性功能減退表型相矛盾，這背后的確切機制尚不清楚。提示下丘腦–垂體–性腺軸的調(diào)控是復(fù)雜的，可能超越了MKRN3- kisspeptin-GnRH軸，也可能存在其他調(diào)節(jié)信號如饑餓素和瘦素的協(xié)調(diào)作用，綜合控制能量平衡和生殖系統(tǒng)[59]。

2.2.2

()是泛素連接酶調(diào)節(jié)因子MAGE家族的成員，對內(nèi)體蛋白再循環(huán)途徑十分重要。突變患者和敲除小鼠模型都復(fù)現(xiàn)了PWS患者下丘腦功能障礙表型[60,61]。敲除的新生小鼠出現(xiàn)胚胎死亡率增加，出生后吸吮不良、生長遲緩、斷奶后體重過度增加、晝夜節(jié)律失調(diào)、青春期延遲以及生育能力下降等表型[62,63]。

下丘腦弓狀核對于調(diào)節(jié)包括攝食在內(nèi)的穩(wěn)態(tài)過程至關(guān)重要。弓狀核包含兩個至關(guān)重要的代謝相關(guān)的神經(jīng)元，前阿片黑素細(xì)胞皮質(zhì)激素(pro-opiomela-nocortin, POMC)神經(jīng)元，主要發(fā)揮抑制攝食的功能，以及刺鼠肽基因相關(guān)(agouti-related peptide, AGRP)神經(jīng)元，發(fā)揮促進攝食的功能。AGRP和POMC神經(jīng)元可以向下丘腦的其他腦區(qū)投射，如室旁核和背側(cè)核，以調(diào)節(jié)進食和能量平衡[64,65]。研究表明，在缺失小鼠中，AGRP在室旁核的投射沒有發(fā)生變化，而與抑制攝食相關(guān)的α黑素細(xì)胞刺激素的纖維顯著減少，表明促進與抑制攝食投射的比例升高，與PWS患者自童年期出現(xiàn)的食欲亢進、攝食過多表型相吻合。是多亞基蛋白質(zhì)復(fù)合物的一部分，與E3泛素連接酶和泛素特異性蛋白酶7共同組成泛素連接酶復(fù)合物，通過泛素化和激活肌動蛋白成核促進因子促進蛋白質(zhì)逆行運輸，從而在肌動蛋白調(diào)控、內(nèi)體分選、軸突生長等途徑發(fā)揮重要作用[66]。因此，缺失可能直接影響了軸突生長和神經(jīng)肽的產(chǎn)生及分泌，進而影響攝食神經(jīng)環(huán)路的功能[67]。

多項研究指出PWS患者催產(chǎn)素的表達(dá)異常，PWS患者死后腦組織分析證實催產(chǎn)素神經(jīng)元數(shù)量減少[68]。缺失小鼠模型也表現(xiàn)出催產(chǎn)素系統(tǒng)的缺陷，催產(chǎn)素神經(jīng)元活動受到抑制[69]。催產(chǎn)素調(diào)控了包括社會認(rèn)知和喂養(yǎng)在內(nèi)的多種行為和生理功能[70]。一方面，催產(chǎn)素可以抑制食物攝入，在攝食行為中作為飽腹神經(jīng)元發(fā)揮著重要作用，另一方面，研究發(fā)現(xiàn)在野生型新生小鼠中注射催產(chǎn)素受體拮抗劑出現(xiàn)與缺失小鼠一致的喂養(yǎng)不足、肌張力低下等表型，在出生后3～5小時單次注射催產(chǎn)素可以挽救突變小鼠的喂養(yǎng)困難[71]。Bischof等[69]發(fā)現(xiàn)的缺失還會引起催產(chǎn)素神經(jīng)元上的興奮性/抑制性突觸比例失衡，造成催產(chǎn)素系統(tǒng)整體功能損傷。此外，泛素特異性蛋白酶7突變的患者常表現(xiàn)出肌張力低下等表型，提示缺失有可能導(dǎo)致泛素連接酶復(fù)合體功能失調(diào)，進而造成 PWS患者嬰幼兒期肌張力低下、吸吮無力[72]。

此外，Kozlov等[73]發(fā)現(xiàn)缺失小鼠下丘腦外側(cè)的食欲素表達(dá)水平和食欲素陽性神經(jīng)元數(shù)量顯著減少。食欲素系統(tǒng)調(diào)節(jié)PWS患者睡眠、晝夜節(jié)律和食物攝入。也是一個參與晝夜節(jié)律調(diào)節(jié)的基因，可以通過抑制節(jié)律調(diào)控蛋白CLOCK (circadian locomotor output cycles kaput)-BMAL1 (brain and muscle aryl hydrocarbon receptor nuclear translocator-like 1)異二聚體的轉(zhuǎn)錄因子活性來調(diào)節(jié)生物鐘。Mercer等[74]發(fā)現(xiàn)缺失導(dǎo)致晝夜節(jié)律和代謝調(diào)控的異常會伴隨著小鼠的生殖功能的低下，雌性小鼠表現(xiàn)為不規(guī)則的發(fā)情周期，雄性小鼠表現(xiàn)出睪丸激素水平的降低。這些結(jié)果表明，缺失與PWS患者的晝夜節(jié)律失調(diào)和性腺發(fā)育不良等表型相關(guān)。

2.2.3

()基因編碼一種在新分化的神經(jīng)元中表達(dá)的核蛋白，可以與調(diào)控細(xì)胞周期的轉(zhuǎn)錄因子E2F1和E2F4相互作用，調(diào)控神經(jīng)元的增殖分化和存活[75～77]。還可以與具有促凋亡活性的抑癌基因相互作用，發(fā)揮抑制細(xì)胞凋亡的功能[78]。研究發(fā)現(xiàn)，缺失小鼠是唯一再現(xiàn)PWS呼吸表型(中樞性呼吸暫停)的動物模型[79]，也與其他下丘腦功能障礙表型相關(guān)，如晝夜節(jié)律失調(diào)、學(xué)習(xí)行為異常、生殖功能低下等。

Andrieu等[80]發(fā)現(xiàn)從E10到E12，所有發(fā)育的神經(jīng)元中都能檢測到，但在E13之后，在神經(jīng)系統(tǒng)的特定腦區(qū)，特別是下丘腦中高表達(dá)，表明可能具有特定的發(fā)育作用。的缺失會干擾5-羥色胺能神經(jīng)前體細(xì)胞的遷移，導(dǎo)致5-羥色胺能神經(jīng)環(huán)路的改變和神經(jīng)元的自發(fā)放電增加，從而引起新生小鼠呼吸暫停[81]。有研究指出PWS患者新生小鼠發(fā)育早期死亡率增加，也是由于前包欽格復(fù)合體產(chǎn)生的異常呼吸節(jié)律導(dǎo)致的[79,82,83]。此外，缺失小鼠下丘腦中催產(chǎn)素和促黃體生成激素釋放激素產(chǎn)生減少[84]，與PWS患者嬰幼兒期喂養(yǎng)困難和性腺發(fā)育不良表型一致[85]。

在背根神經(jīng)節(jié)的神經(jīng)生長因子(nerve growth factor, NGF)依賴性神經(jīng)元中高度表達(dá)，介導(dǎo)NGF依賴性感覺神經(jīng)元的終末分化和存活[86]，是NGF依賴性感覺神經(jīng)元的發(fā)育所必需的。還可以與對位肌球蛋白相關(guān)激酶A (tropomyosin-related kinase A, TrkA)受體酪氨酸激酶和p75神經(jīng)營養(yǎng)蛋白受體相互作用，促進NGF/TrkA信號傳導(dǎo)。缺失的小鼠表現(xiàn)出NGF依賴性神經(jīng)元的發(fā)育受損，出現(xiàn)與PWS患者一致的對熱誘導(dǎo)疼痛的高耐受性。

此外，作為MAGE家族的成員之一，在視交叉上核中高度表達(dá)，提示它很有可能在晝夜節(jié)律調(diào)節(jié)中發(fā)揮作用。Lu等[87]研究發(fā)現(xiàn)可以與核心生物鐘基因相互作用，缺失使BMAL1通過泛素–蛋白酶體系統(tǒng)被降解，導(dǎo)致PWS患者睡眠節(jié)律失調(diào)，出現(xiàn)快動眼睡眠障礙。中樞和外周生物鐘失衡還會導(dǎo)致日常節(jié)律的紊亂，影響代謝和內(nèi)分泌系統(tǒng)等[88]。

2.2.4

在PWS關(guān)鍵基因組區(qū)，包含一類存在于細(xì)胞核仁的非編碼RNA。越來越多的研究表明非編碼RNA參與調(diào)節(jié)轉(zhuǎn)錄后修飾過程[89]。在這類非編碼RNA中，()與PWS的下丘腦功能高度相關(guān)。缺失小鼠模型復(fù)現(xiàn)了PWS患者肌張力低下、生長發(fā)育遲緩、食欲亢進、睡眠障礙等諸多表型[90]。

在中樞神經(jīng)系統(tǒng)與攝食神經(jīng)環(huán)路相關(guān)的腦區(qū)中高度表達(dá)，特別是弓狀核和室旁核。缺失小鼠表現(xiàn)出病態(tài)的肥胖和強迫性攝食行為[91,92]。如果靶向敲除NPY神經(jīng)元中基因表達(dá)，可以重復(fù)缺失小鼠的下丘腦功能障礙表型，包括出生后生長發(fā)育不良、體重持續(xù)增長和食欲亢進等，表明基因在NPY神經(jīng)元中起著關(guān)鍵作用。而NPY神經(jīng)元作為下丘腦攝食神經(jīng)環(huán)路的重要組成部分，與攝食調(diào)節(jié)密切相關(guān)，的缺失會導(dǎo)致NPY mRNA表達(dá)上調(diào)，與食物攝入量的顯著增加的表現(xiàn)一致[93]。通過腺病毒將基因產(chǎn)物注射到下丘腦，可以在一定程度上挽救缺失小鼠的肥胖表型[94]。此外，只有在發(fā)育早期缺失的小鼠會發(fā)展為食欲亢進，而在成年時期誘導(dǎo)的缺失，小鼠則表現(xiàn)出正常的生長發(fā)育和體重，以及食物攝入量的減少，提示還可能參與攝食環(huán)路的發(fā)育過程[95,96]。目前對調(diào)控NPY神經(jīng)元以及下丘腦攝食神經(jīng)環(huán)路的具體機制尚不清楚，部分證據(jù)提示可能與RNA修飾和剪接有關(guān)[97]，隨著研究的不斷深入，繼續(xù)鑒定的靶標(biāo)RNA及其調(diào)控的修飾類型，也有助于我們進一步認(rèn)識到非編碼RNA在調(diào)節(jié)生長發(fā)育和食欲控制方面的重要作用。

缺失小鼠會出現(xiàn)快動眼睡眠的失調(diào)，復(fù)現(xiàn)了PWS患者睡眠障礙的表型[98,99]。食欲素神經(jīng)元和黑色素濃集激素神經(jīng)元位于下丘腦外側(cè)，在整個中樞神經(jīng)系統(tǒng)中具有廣泛投射，調(diào)節(jié)睡眠-覺醒系統(tǒng)。食欲素神經(jīng)元可以調(diào)控其他促進覺醒的神經(jīng)元信號，發(fā)揮抑制快動眼睡眠的作用，而黑色素濃集激素神經(jīng)元能夠增加快動眼睡眠，提升睡眠質(zhì)量[100]。食欲素敲除小鼠模型也會表現(xiàn)出相似的快動眼睡眠失調(diào)[101]。缺失小鼠中食欲素神經(jīng)元與黑色素濃集激素神經(jīng)元比例失衡可能與快動眼睡眠失調(diào)相關(guān)。此外，DNA甲基化對日常生物鐘節(jié)律具有重要作用，大腦中CpG二核苷酸的一個亞群表現(xiàn)出晝夜節(jié)律性甲基化。而缺失小鼠中晝夜節(jié)律性DNA甲基化位點被破壞，可能通過協(xié)調(diào)大腦中一些表觀遺傳因子的節(jié)律模式而調(diào)節(jié)晝夜節(jié)律和睡眠[102]。睡眠的調(diào)節(jié)與體溫和攝食相關(guān)的功能也密不可分，如睡眠期間常伴有體溫的下降等[103]，缺失小鼠同樣觀察到與PWS患者一致的體溫調(diào)節(jié)障礙[104,105]。

2.3 Angelman綜合征區(qū)缺失

Angelman綜合征區(qū)包含兩個僅由母系染色體表達(dá)的基因和。已被確定為是導(dǎo)致Angelman綜合征表型的關(guān)鍵基因。Angelman綜合征的特征是小頭畸形、步態(tài)共濟失調(diào)、嚴(yán)重智力和言語缺陷、睡眠障礙等，其15q11～13的缺失發(fā)生在母系染色體上[2]。

2.4 遠(yuǎn)端非印記區(qū)缺失

在15q11～13遠(yuǎn)端非印記區(qū)發(fā)現(xiàn)的基因包括一組γ-氨基丁酸受體亞基()、和基因。和在父系和母系等位基因中同等表達(dá)，基因與眼部和皮毛色素沉著有關(guān)，的父系缺失可能導(dǎo)致PWS患者色素減退等癥狀[106]。是編碼鳥嘌呤核苷酸交換因子的重要基因[107]。Ji等[108]的研究發(fā)現(xiàn)突變與小鼠神經(jīng)肌肉無力、精子頂體發(fā)育缺陷相關(guān)?？赡芡ㄟ^參與細(xì)胞的蛋白質(zhì)囊泡運輸和降解途徑，與PWS患者嬰幼兒期吸吮無力、生長發(fā)育遲緩、性腺發(fā)育不良等表型相關(guān)。

γ-氨基丁酸是中樞神經(jīng)系統(tǒng)中一類重要的抑制性神經(jīng)遞質(zhì)。15q11～13遠(yuǎn)端非印記區(qū)的受體亞基等位基因表達(dá)上存在父系偏移，即PWS患者中父系等位基因的缺失使這一類受體亞基基因表達(dá)減少大于50%。而GABA能機制與PWS許多下丘腦功能障礙表型相關(guān)，包括過度的攝食、強迫行為和學(xué)習(xí)記憶等[109～111]。

綜上所述，盡管PWS被認(rèn)為是一種連續(xù)基因缺失綜合征，但基因和臨床表現(xiàn)之間的對應(yīng)關(guān)系和詳細(xì)機制仍有待研究。、、、、、、和等基因與PWS下丘腦功能障礙表型密不可分(表1)。而了解PWS候選基因的表達(dá)、功能以及它們在轉(zhuǎn)錄、翻譯過程中涉及的基因之間相互作用，將提高我們對PWS基因型和下丘腦相關(guān)表型之間的理解，為治療方案改善和藥物靶點發(fā)現(xiàn)提供新的見解和認(rèn)識。

3 結(jié)語與展望

PWS是一種復(fù)雜的神經(jīng)發(fā)育性疾病，對內(nèi)分泌系統(tǒng)、神經(jīng)系統(tǒng)以及認(rèn)知和行為產(chǎn)生嚴(yán)重的影響。到目前為止，對癥治療仍是PWS患者的唯一選擇。PWS患者的臨床表型復(fù)雜，因此，根據(jù)不同基因缺陷所對應(yīng)的表型對患者進行及早診斷和進一步的基因分型有助于針對性治療的開展。同時，新的藥物靶標(biāo)發(fā)現(xiàn)與新治療方式的探索也基于對致病機制研究的不斷深入?；蛑委熀捅碛^遺傳學(xué)療法具有廣泛的應(yīng)用的前景。在PWS患者來源的細(xì)胞模型和模擬PWS的動物模型上，組蛋白甲基轉(zhuǎn)移酶G9a抑制劑能夠重新激活父系染色體的表達(dá)，挽救PWS小鼠模型中出生后發(fā)育不良和生長遲緩等表型[112,113]。此外，基于誘導(dǎo)多能干細(xì)胞的下丘腦類器官培養(yǎng)也為PWS 的下丘腦發(fā)育機制研究和藥物篩選提供了可能的平臺[114]。因此，未來研究中應(yīng)進一步建立能模擬PWS的體內(nèi)外動物與細(xì)胞模型，探究PWS下丘腦功能障礙表型背后的分子機制和可干預(yù)靶點，對潛在治療藥物進行篩選，探索新的治療手段，同時評估這些治療方法臨床應(yīng)用的可行性，也有望為其他相關(guān)的代謝和神經(jīng)發(fā)育性疾病的研究提供借鑒和思考。

表1 Prader-Willi綜合征中基因功能和下丘腦功能障礙表型相關(guān)研究

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Advances in genetic mechanisms of hypothalamic dysfunction in Prader-Willi syndrome

Xinyuan Wang, Rui Sun, Yuanqing Gao

Prader-Willi syndrome (PWS) is a rare congenital developmental disorder mainly due to the absent expression of genes on the paternally inherited chromosome 15q11–q13 region. Most of the clinical symptoms of PWS are related to hypothalamic dysfunction, including hyperphagia, morbid obesity, mental retardation, and hypogonadism. However, the molecular genetic mechanism of PWS is not fully understood, especially the relationship between genotype and phenotype. In this review, we focus on the genetic mechanisms behind the hypothalamus dysfunction, summarizing the latest research progress of the roles of PWS candidate genes in chromosome 15q11–q13 region (,,,,,,and) in hypothalamic disorders such as hyperphagia and obesity, hypogonadism, sleep-disordered breathing, growth retardation in PWS patients, to deepen the understanding of PWS syndrome and explore potential new drug targets.

Prader-Willi syndrome; hypothalamus; genetic mechanism

2022-06-30;

2022-07-28;

2022-08-11

國家自然科學(xué)基金項目(編號：81873654)資助[Supported by the National Natural Science Foundation of China (No. 81873654)]

王心緣，在讀碩士研究生，專業(yè)方向：藥理學(xué)。E-mail: darlingxyxy@163.com

高原青，博士，教授，研究方向：神經(jīng)藥理。E-mail: yuanqinggao@njmu.edu.cn

10.16288/j.yczz.22-188

(責(zé)任編委: 孟卓賢)