Prader-Willi综合征下丘脑功能障碍的遗传机制研究进展

王心缘，孙睿，高原青

综 述

Prader-Willi综合征下丘脑功能障碍的遗传机制研究进展

王心缘，孙睿，高原青

南京医科大学药学院，江苏省心脑血管药物重点实验室，南京 211166

Prader-Willi 综合征(Prader-Willi syndrome, PWS)是一种罕见的先天发育性疾病，主要由父系15号染色体长臂15q11～q13区域基因缺失或沉默引起。PWS临床表型复杂，主要包括无法满足的饥饿、病态的肥胖、智力发育迟缓、性腺发育不良等，多数症状提示与下丘脑的功能障碍相关。然而到目前为止，PWS的分子遗传机制尚不明确，尤其是基因和临床表现之间的对应关系和详细机制有待进一步研究。本文以PWS“基因型–下丘脑功能障碍表型”之间的关联为重点，综述了15q11～q13区域基因(、、、、、、和等)与PWS患者过度摄食和肥胖、性腺发育不良、睡眠呼吸障碍、生长发育迟缓等表型相关的研究进展，旨在加深对PWS遗传机制的理解，探讨潜在的PWS药物靶点的可能性。

Prader-Willi 综合征；下丘脑；遗传机制

Prader-Willi综合征(Prader-Willi syndrome, PWS)又称小胖–威利综合征，是一种罕见的、多系统的神经发育性疾病。1956年，Prader等[1]根据特有的临床表型首次报道了9名具有该疾病特征的患者。65%～75%的典型PWS患者与父系15q11～q13区域基因缺失有关，20%～30%具有母系同源二倍体，1%～ 3%的不典型PWS患者由15号染色体重排或印记缺陷引起[2]。PWS每年的发病率约为1/10,000～1/30,000，目前尚没有办法根治，只能对症治疗，且终身需要照料和监管，给患者和家庭带来极大的负担。由于PWS的很多临床特征与其他代谢和发育疾病有重合，根据临床表现对PWS做出早期诊断比较困难，容易出现儿童期漏诊以及成年期肥胖患者误诊，因此对可疑病患进行基因检测是目前PWS诊断的重要手段[3]。

PWS临床表型复杂，从胎儿到成年期表现出不同症状。胎儿期胎动减少，多发生早产或难产；新生儿期出现肌张力低下、吸吮无力、喂养困难、生长缓慢、外生殖器发育不良等；儿童期一般表现为身材矮小、近视、肤色较浅、龋齿、智力障碍和行为问题，一般自8岁起开始出现无节制饮食并导致超重或肥胖；青春期和成年期肥胖体型会更加明显，伴随由于肥胖所引起的一系列并发症，以及性腺发育不良、骨质疏松、脊柱侧凸、嗜睡和抑郁等症状[4,5]。下丘脑是人体基础代谢功能的调控中心。PWS的许多表型与下丘脑功能障碍密切相关，如体重和摄食异常、体温调节异常、性腺发育不良、内分泌功能紊乱等[6～10]，由过度摄食所引起的肥胖及其并发症也是造成PWS患者死亡的重要因素[11]。然而，PWS下丘脑功能障碍与缺失区域基因的功能之间的关系尚未被完全阐明。本文主要对下丘脑功能障碍相关的遗传证据及其研究进展展开了综述，以期为PWS的诊断和治疗提供借鉴和参考。

1 PWS下丘脑功能障碍表型

1.1 过度摄食和肥胖

Miller等[12]将PWS患者病程分为7个不同的营养阶段。在新生儿早期和婴儿期，PWS患者主要表现为肌张力低下、吸吮不良、喂养困难，容易出现生长迟缓或停滞，甚至可能死亡。在2～4岁时，PWS患者食欲和正常儿童无明显区别，体重开始增长；4～8岁时，食欲和体重异常增加，一般自8岁起，PWS患者开始出现持续的食欲亢进，缺乏正常的饱腹感。在这个阶段通常需要一对一的监督管理，以防止由于暴饮暴食导致的胃破裂、胃坏死和窒息死亡[13]。食欲亢进、过度摄食常常导致PWS患者出现早发性病态肥胖和相关并发症，这是PWS死亡的常见原因[14]。目前对PWS患者婴幼儿期喂养不良、儿童期开始出现过度摄食和肥胖的病理机制仍不清楚。早期的饮食治疗和长期的营养监测可以改善PWS患者的预后，包括婴幼儿期通过辅助喂养保证足够的能量摄入，通过身体活动和饮食管理预防PWS肥胖等，至今尚没有药物可以帮助控制食欲。减重手术曾被认为是重要的对症治疗方案，但是关于手术的有效性存在较大争议，并且手术无法改善患者的饱腹感缺失和过度摄食行为，所以目前尚不推荐该手术用于常规治疗[15,16]。

1.2 性腺功能减退

性腺功能减退通常被认为是下丘脑功能障碍和原发性性腺功能低下共同导致的。大多数患者从新生儿期开始出现并伴随一生，表现为外生殖器发育不良。在男性中最典型的表现是阴囊发育不良，阴囊较小，单侧或双侧隐睾症见于80%～90%的男性患者[17]，女性主要表现为阴唇阴蒂发育不全[9]；青春期PWS患者通常出现青春期发育不完全、青春期发育延迟，有极少数PWS病例会伴有中枢性早熟；成年期PWS患者多表现为不孕不育、原发性闭经、月经稀疏等。PWS男性隐睾和外生殖器发育不良患者，在出生后早期注射睾酮或人绒毛膜促性腺激素可以改善阴茎大小、促进阴囊发育、协助调整睾丸位置下降到阴囊等，近端型隐睾和远端型隐睾人绒毛膜促性腺激素疗效不佳者可以考虑外科手术治疗[18,19]。对于PWS患者性激素替代治疗以诱导或促进青春期发育目前尚无统一的共识，且替代治疗药物通常价格昂贵，用药依从性和副作用问题较大，需要充分考虑利弊并积极探索更优化的治疗方案。

1.3 睡眠呼吸障碍

PWS患者表现为明显的昼夜节律失调性睡眠障碍、睡眠中断和睡眠呼吸障碍。有研究表明睡眠呼吸障碍还与神经认知功能的显著缺陷有关，包括PWS患者的注意力不集中、白天过度嗜睡和易激惹等表现[20]。许多PWS患者患有阻塞性、中枢性和混合性睡眠呼吸暂停综合征。肥胖、肌张力低下、气道狭窄、脊柱侧弯等被列为影响PWS睡眠呼吸障碍严重程度的重要因素[21]。下丘脑是睡眠觉醒和昼夜节律的重要调控中枢，多项研究也表明，PWS患者睡眠呼吸障碍与下丘脑功能失调相关，如下丘脑食欲素神经元总数和编码食欲素前体的基因表达水平发生了显著变化，食欲素系统与睡眠障碍和认知功能密切相关[22,23]。兴奋剂药物(莫达非尼、哌醋甲酯或苯丙胺盐混合物)已被证明可改善发作性睡病患者的日间过度嗜睡[24]。对PWS引起的呼吸障碍，目前多为手术治疗，如腺扁桃体切除术联合持续气道正压通气等[25]。

1.4 生长发育迟缓

40%～100%的PWS患儿因生长激素缺乏导致身材矮小，一般自婴儿时期即会出现[5]。儿童时期表现为小手和小脚，语言和运动系统也较同龄人发育缓慢；学龄期表现出严重的学习困难，伴有一系列的行为问题，如易怒、固执、脾气暴躁等[4,26]。到其青春期和成年期，PWS患者身高明显低于正常水平，还常伴有脊柱侧弯、骨质疏松等多系统受累症状[27]。有研究指出，PWS患者在童年时期接受生长激素治疗后，能够达到正常的成年身高，还可以减缓PWS患者行为问题的发展[28]。重组人生长激素于2000年得到美国食品药品监督管理局批准，用于治疗PWS患者的生长发育障碍[29]。

2 PWS基因型和表型的关系

典型的PWS综合征患者是与父系15号染色体长臂区域基因缺失有关。到目前为止，尚未发现有单一的基因突变可以导致这种遗传性疾病的所有表型。染色体15q11～q13区域由着丝粒至端粒方向可分为四组基因：(1)位于BP1～BP2断点之间的近端非印迹区域，包含4个双亲同等表达基因：、、、；(2) PWS仅父系表达印记区域：包含五个蛋白质编码基因(、、、、)、一个基因簇和几个反义转录本；(3)含有母系优先表达基因的Angelman综合征区域：和；(4)远端非印记区域：包含3个受体亚基、和[30]。根据缺失区域的不同PWS又可分为I型和II型，包含BP2～BP3区域基因缺失的为II型，I型相比于II型额外缺失了BP1～BP2非印记区域[31](图1)。研究发现，I型PWS患者与II型相比，具有更严重的智力障碍和行为问题[32,33]，很有可能是由于额外缺失的非印记区基因所引起的。本文将详细总结染色体15q11～q13区域中与下丘脑功能障碍密切相关的基因的研究进展。

图1 15q11～q13区域基因表达示意图

2.1 近端非印记区缺失

15号染色体近端非印记区包含4个在父系和母系等位基因中同等表达的基因，PWS患者表现为父系染色体上的基因缺失。只包含这4个非印记区基因缺失的疾病被称为15q11.2 BP1～BP2微缺失综合征[34]，Butler等[35]报告了200多例15q11.2 BP1～BP2微缺失患者，多表现为发育迟缓、语言障碍、运动功能减退和自闭症谱系障碍等。

2.1.1

()基因编码镁离子转运蛋白，在大脑中表达量最高。Chang等[36]发现15q11.2 BP1～BP2微重复与神经性厌食症密切相关，介导的镁离子转运失调是其中的重要机制，由此猜测，的父系缺失可能与PWS患者食欲亢进、过度摄食相关，而婴儿期喂养困难、吸吮无力可能是其他基因缺失的结果。Chen等[37]的报告则表明，PWS患者的下丘脑神经分泌颗粒和神经肽的产生减少，虽然作者将这种减少解释为的缺失，但NIPA1蛋白与内体的共定位表明其也与分泌途径相关，可能与协同作用，缺失会阻碍神经元的成熟和分泌，影响到下丘脑功能[38]。

2.1.2

在结构和功能上与类似，编码镁离子转运蛋白，定位于内体、神经元和内皮细胞表面质膜上[39]。基因突变可以引起儿童癫痫，与大脑发育迟缓、神经精神异常等表型密切相关。神经元兴奋性由各种受体和离子通道调节，编码镁离子转运蛋白，其缺失会降低大电导钾离子通道电流，增强神经元的兴奋性，影响神经元的稳态和功能，进而影响到大脑发育和精神状况[40]。在小鼠和2型糖尿病骨质疏松症的体外模型中，也观察到表达降低，可能通过调节线粒体自噬途径在2型糖尿病中积极调节成骨细胞的成骨能力[41]，这与PWS患者青春期及成年期过度肥胖常伴随糖尿病和骨质疏松等表型一致。此外，小鼠骨质疏松症的机制复杂，不能排除瘦素信号在其中所起的作用。瘦素与位于下丘脑的瘦素受体结合，通过中枢途径调控骨骼形成和摄食环路，而表达降低很有可能影响瘦素系统功能，进而影响到下丘脑对成骨过程的调控[42]。

2.1.3

()是γ-微管蛋白复合物的核心成分，是中心体微管成核所必需的[43]。基因突变与原发性小头症和神经发育迟缓相关[44]。Wolf等[45]通过基因组分析认为对神经精神疾病患者的强迫行为有贡献，可能与PWS患者强迫性摄食和行为问题相关。TUBGCP5蛋白在心脏，骨骼肌和大脑中表达最高，参与细胞分裂的关键过程，但与PWS患者相关的下丘脑功能障碍表型的具体机制仍有待进一步研究。

2.1.4

()参与调节细胞骨架动力学和蛋白质翻译。早期的研究表明，具有PWS样症状的脆性X染色体综合征患者的mRNA表达水平通常降低了两到四倍，提示表达的降低可能与更严重的神经发育障碍相关[46]。近期的一项研究表明，单倍体不足小鼠表现出强迫性行为和饮食紊乱[47]。

CYFIP1在细胞内是WAVE复合体(Wiskott- Aldrich syndrome protein-family Verprolin homologous protein, WAVE)的组成蛋白之一。WAVE复合体本身对其下游的肌动蛋白成核因子(Actin-related protein 2/3 complex, Arp2/3)无直接活性，但可以通过CYFIP1转导Rac信号，诱导WAVE复合体构象发生变化，触发Arp2/3成核，调控肌动蛋白和细胞骨架[48]。单倍体不足小鼠表现出突触功能障碍、肌动蛋白聚合异常，可能因此影响到神经元稳态和功能[49]。此外，有研究表明，髓鞘形成的早期阶段少突胶质细胞的成熟和髓鞘包裹的启动需要Arp2/3组装肌动蛋白[50]，而的缺失很有可能影响髓鞘生发和动作电位的快速传播，进而影响学习记忆等行为，与PWS生长发育迟缓、智力障碍表型密切相关。

CYFIP1还可以与脆性X智力低下蛋白(Fragile X mental retardation protein, FMRP)和翻译起始因4E (eukaryotic translation initiation factor 4E, eIF4E)相互作用[51]。eIF4E是帽结合蛋白，与解旋酶eIF4A和支架蛋白eIF4G等蛋白质协同作用，与mRNA结合，调控核糖体募集和翻译起始，CYFIP1-eIF4E- FMR1复合物的活性调控蛋白质翻译过程[52]。Conn等[53]的研究指出调控eIF4E可以抑制高脂食物引起的肥胖症和脂肪肝，由此推测的缺失很有可能引起eIF4E过表达，进而引起PWS患者食欲亢进和病态肥胖。

2.2 PWS仅父系表达印记区缺失

2.2.1

()是第一个对促性腺激素释放激素(Gonadotropin-releasing hor­mone, GnRH)分泌具有抑制作用的基因[54]。缺失患者表现为中枢性早熟的典型特征[55]。与蛋白质泛素化有关，发挥着信号转导、细胞周期调控、细胞分化等作用。在婴儿期和幼年期下丘脑弓状核kisspeptin神经元中高度表达，很可能通过泛素化修饰调控kisspeptin和速激肽3的启动子活性，抑制GnRH的分泌。在青春期开始前表达减少，减少对GnRH分泌的抑制，调控青春期的发育[56]。然而，中枢性早熟在PWS患者中较为罕见[57]。Ludwig等[58]曾报道过一例用促性腺激素释放激素类似物和重组人生长激素联合治疗罕见的中枢性早熟PWS患者，证明促性腺激素释放激素类似物对这种特殊的PWS患者青春期发育状况有益。

典型的PWS患者以外生殖器发育不良和低促性腺激素、性腺功能减退为特征。的缺失与典型PWS患者性腺发育不良、性功能减退表型相矛盾，这背后的确切机制尚不清楚。提示下丘脑–垂体–性腺轴的调控是复杂的，可能超越了MKRN3- kisspeptin-GnRH轴，也可能存在其他调节信号如饥饿素和瘦素的协调作用，综合控制能量平衡和生殖系统[59]。

2.2.2

()是泛素连接酶调节因子MAGE家族的成员，对内体蛋白再循环途径十分重要。突变患者和敲除小鼠模型都复现了PWS患者下丘脑功能障碍表型[60,61]。敲除的新生小鼠出现胚胎死亡率增加，出生后吸吮不良、生长迟缓、断奶后体重过度增加、昼夜节律失调、青春期延迟以及生育能力下降等表型[62,63]。

下丘脑弓状核对于调节包括摄食在内的稳态过程至关重要。弓状核包含两个至关重要的代谢相关的神经元，前阿片黑素细胞皮质激素(pro-opiomela­nocortin, POMC)神经元，主要发挥抑制摄食的功能，以及刺鼠肽基因相关(agouti-related peptide, AGRP)神经元，发挥促进摄食的功能。AGRP和POMC神经元可以向下丘脑的其他脑区投射，如室旁核和背侧核，以调节进食和能量平衡[64,65]。研究表明，在缺失小鼠中，AGRP在室旁核的投射没有发生变化，而与抑制摄食相关的α黑素细胞刺激素的纤维显著减少，表明促进与抑制摄食投射的比例升高，与PWS患者自童年期出现的食欲亢进、摄食过多表型相吻合。是多亚基蛋白质复合物的一部分，与E3泛素连接酶和泛素特异性蛋白酶7共同组成泛素连接酶复合物，通过泛素化和激活肌动蛋白成核促进因子促进蛋白质逆行运输，从而在肌动蛋白调控、内体分选、轴突生长等途径发挥重要作用[66]。因此，缺失可能直接影响了轴突生长和神经肽的产生及分泌，进而影响摄食神经环路的功能[67]。

多项研究指出PWS患者催产素的表达异常，PWS患者死后脑组织分析证实催产素神经元数量减少[68]。缺失小鼠模型也表现出催产素系统的缺陷，催产素神经元活动受到抑制[69]。催产素调控了包括社会认知和喂养在内的多种行为和生理功能[70]。一方面，催产素可以抑制食物摄入，在摄食行为中作为饱腹神经元发挥着重要作用，另一方面，研究发现在野生型新生小鼠中注射催产素受体拮抗剂出现与缺失小鼠一致的喂养不足、肌张力低下等表型，在出生后3～5小时单次注射催产素可以挽救突变小鼠的喂养困难[71]。Bischof等[69]发现的缺失还会引起催产素神经元上的兴奋性/抑制性突触比例失衡，造成催产素系统整体功能损伤。此外，泛素特异性蛋白酶7突变的患者常表现出肌张力低下等表型，提示缺失有可能导致泛素连接酶复合体功能失调，进而造成 PWS患者婴幼儿期肌张力低下、吸吮无力[72]。

此外，Kozlov等[73]发现缺失小鼠下丘脑外侧的食欲素表达水平和食欲素阳性神经元数量显著减少。食欲素系统调节PWS患者睡眠、昼夜节律和食物摄入。也是一个参与昼夜节律调节的基因，可以通过抑制节律调控蛋白CLOCK (circadian locomotor output cycles kaput)-BMAL1 (brain and muscle aryl hydrocarbon receptor nuclear translocator-like 1)异二聚体的转录因子活性来调节生物钟。Mercer等[74]发现缺失导致昼夜节律和代谢调控的异常会伴随着小鼠的生殖功能的低下，雌性小鼠表现为不规则的发情周期，雄性小鼠表现出睾丸激素水平的降低。这些结果表明，缺失与PWS患者的昼夜节律失调和性腺发育不良等表型相关。

2.2.3

()基因编码一种在新分化的神经元中表达的核蛋白，可以与调控细胞周期的转录因子E2F1和E2F4相互作用，调控神经元的增殖分化和存活[75～77]。还可以与具有促凋亡活性的抑癌基因相互作用，发挥抑制细胞凋亡的功能[78]。研究发现，缺失小鼠是唯一再现PWS呼吸表型(中枢性呼吸暂停)的动物模型[79]，也与其他下丘脑功能障碍表型相关，如昼夜节律失调、学习行为异常、生殖功能低下等。

Andrieu等[80]发现从E10到E12，所有发育的神经元中都能检测到，但在E13之后，在神经系统的特定脑区，特别是下丘脑中高表达，表明可能具有特定的发育作用。的缺失会干扰5-羟色胺能神经前体细胞的迁移，导致5-羟色胺能神经环路的改变和神经元的自发放电增加，从而引起新生小鼠呼吸暂停[81]。有研究指出PWS患者新生小鼠发育早期死亡率增加，也是由于前包钦格复合体产生的异常呼吸节律导致的[79,82,83]。此外，缺失小鼠下丘脑中催产素和促黄体生成激素释放激素产生减少[84]，与PWS患者婴幼儿期喂养困难和性腺发育不良表型一致[85]。

在背根神经节的神经生长因子(nerve growth factor, NGF)依赖性神经元中高度表达，介导NGF依赖性感觉神经元的终末分化和存活[86]，是NGF依赖性感觉神经元的发育所必需的。还可以与对位肌球蛋白相关激酶A (tropomyosin-related kinase A, TrkA)受体酪氨酸激酶和p75神经营养蛋白受体相互作用，促进NGF/TrkA信号传导。缺失的小鼠表现出NGF依赖性神经元的发育受损，出现与PWS患者一致的对热诱导疼痛的高耐受性。

此外，作为MAGE家族的成员之一，在视交叉上核中高度表达，提示它很有可能在昼夜节律调节中发挥作用。Lu等[87]研究发现可以与核心生物钟基因相互作用，缺失使BMAL1通过泛素–蛋白酶体系统被降解，导致PWS患者睡眠节律失调，出现快动眼睡眠障碍。中枢和外周生物钟失衡还会导致日常节律的紊乱，影响代谢和内分泌系统等[88]。

2.2.4

在PWS关键基因组区，包含一类存在于细胞核仁的非编码RNA。越来越多的研究表明非编码RNA参与调节转录后修饰过程[89]。在这类非编码RNA中，()与PWS的下丘脑功能高度相关。缺失小鼠模型复现了PWS患者肌张力低下、生长发育迟缓、食欲亢进、睡眠障碍等诸多表型[90]。

在中枢神经系统与摄食神经环路相关的脑区中高度表达，特别是弓状核和室旁核。缺失小鼠表现出病态的肥胖和强迫性摄食行为[91,92]。如果靶向敲除NPY神经元中基因表达，可以重复缺失小鼠的下丘脑功能障碍表型，包括出生后生长发育不良、体重持续增长和食欲亢进等，表明基因在NPY神经元中起着关键作用。而NPY神经元作为下丘脑摄食神经环路的重要组成部分，与摄食调节密切相关，的缺失会导致NPY mRNA表达上调，与食物摄入量的显著增加的表现一致[93]。通过腺病毒将基因产物注射到下丘脑，可以在一定程度上挽救缺失小鼠的肥胖表型[94]。此外，只有在发育早期缺失的小鼠会发展为食欲亢进，而在成年时期诱导的缺失，小鼠则表现出正常的生长发育和体重，以及食物摄入量的减少，提示还可能参与摄食环路的发育过程[95,96]。目前对调控NPY神经元以及下丘脑摄食神经环路的具体机制尚不清楚，部分证据提示可能与RNA修饰和剪接有关[97]，随着研究的不断深入，继续鉴定的靶标RNA及其调控的修饰类型，也有助于我们进一步认识到非编码RNA在调节生长发育和食欲控制方面的重要作用。

缺失小鼠会出现快动眼睡眠的失调，复现了PWS患者睡眠障碍的表型[98,99]。食欲素神经元和黑色素浓集激素神经元位于下丘脑外侧，在整个中枢神经系统中具有广泛投射，调节睡眠-觉醒系统。食欲素神经元可以调控其他促进觉醒的神经元信号，发挥抑制快动眼睡眠的作用，而黑色素浓集激素神经元能够增加快动眼睡眠，提升睡眠质量[100]。食欲素敲除小鼠模型也会表现出相似的快动眼睡眠失调[101]。缺失小鼠中食欲素神经元与黑色素浓集激素神经元比例失衡可能与快动眼睡眠失调相关。此外，DNA甲基化对日常生物钟节律具有重要作用，大脑中CpG二核苷酸的一个亚群表现出昼夜节律性甲基化。而缺失小鼠中昼夜节律性DNA甲基化位点被破坏，可能通过协调大脑中一些表观遗传因子的节律模式而调节昼夜节律和睡眠[102]。睡眠的调节与体温和摄食相关的功能也密不可分，如睡眠期间常伴有体温的下降等[103]，缺失小鼠同样观察到与PWS患者一致的体温调节障碍[104,105]。

2.3 Angelman综合征区缺失

Angelman综合征区包含两个仅由母系染色体表达的基因和。已被确定为是导致Angelman综合征表型的关键基因。Angelman综合征的特征是小头畸形、步态共济失调、严重智力和言语缺陷、睡眠障碍等，其15q11～13的缺失发生在母系染色体上[2]。

2.4 远端非印记区缺失

在15q11～13远端非印记区发现的基因包括一组γ-氨基丁酸受体亚基()、和基因。和在父系和母系等位基因中同等表达，基因与眼部和皮毛色素沉着有关，的父系缺失可能导致PWS患者色素减退等症状[106]。是编码鸟嘌呤核苷酸交换因子的重要基因[107]。Ji等[108]的研究发现突变与小鼠神经肌肉无力、精子顶体发育缺陷相关。可能通过参与细胞的蛋白质囊泡运输和降解途径，与PWS患者婴幼儿期吸吮无力、生长发育迟缓、性腺发育不良等表型相关。

γ-氨基丁酸是中枢神经系统中一类重要的抑制性神经递质。15q11～13远端非印记区的受体亚基等位基因表达上存在父系偏移，即PWS患者中父系等位基因的缺失使这一类受体亚基基因表达减少大于50%。而GABA能机制与PWS许多下丘脑功能障碍表型相关，包括过度的摄食、强迫行为和学习记忆等[109～111]。

综上所述，尽管PWS被认为是一种连续基因缺失综合征，但基因和临床表现之间的对应关系和详细机制仍有待研究。、、、、、、和等基因与PWS下丘脑功能障碍表型密不可分(表1)。而了解PWS候选基因的表达、功能以及它们在转录、翻译过程中涉及的基因之间相互作用，将提高我们对PWS基因型和下丘脑相关表型之间的理解，为治疗方案改善和药物靶点发现提供新的见解和认识。

3 结语与展望

PWS是一种复杂的神经发育性疾病，对内分泌系统、神经系统以及认知和行为产生严重的影响。到目前为止，对症治疗仍是PWS患者的唯一选择。PWS患者的临床表型复杂，因此，根据不同基因缺陷所对应的表型对患者进行及早诊断和进一步的基因分型有助于针对性治疗的开展。同时，新的药物靶标发现与新治疗方式的探索也基于对致病机制研究的不断深入。基因治疗和表观遗传学疗法具有广泛的应用的前景。在PWS患者来源的细胞模型和模拟PWS的动物模型上，组蛋白甲基转移酶G9a抑制剂能够重新激活父系染色体的表达，挽救PWS小鼠模型中出生后发育不良和生长迟缓等表型[112,113]。此外，基于诱导多能干细胞的下丘脑类器官培养也为PWS 的下丘脑发育机制研究和药物筛选提供了可能的平台[114]。因此，未来研究中应进一步建立能模拟PWS的体内外动物与细胞模型，探究PWS下丘脑功能障碍表型背后的分子机制和可干预靶点，对潜在治疗药物进行筛选，探索新的治疗手段，同时评估这些治疗方法临床应用的可行性，也有望为其他相关的代谢和神经发育性疾病的研究提供借鉴和思考。

表1 Prader-Willi综合征中基因功能和下丘脑功能障碍表型相关研究

[1] Prader A. Ein syndrom von adipositas, kleinwuchs, kryptorchismus und oligophrenie nach myatonieartigem zustand im neugeborenenalter., 1956, (86): 1260–1261.

[2] Buiting K. Prader-Willi syndrome and Angelman syndrome.,2010, 154C(3): 365–376.

[3] Holm VA, Cassidy SB, Butler MG, Hanchett JM, Greenswag LR, Whitman BY, Greenberg F. Prader-Willi syndrome: consensus diagnostic criteria.,1993, 91(2): 398–402.

[4] Bittel DC, Butler MG. Prader-Willi syndrome: clinical genetics, cytogenetics and molecular biology.,2005, 7(14): 1–20.

[5] Division of endocrinology, genetics and metabolism, Chinese Pediatric Society, Chinese Medical Association, Editorial board of Chinese Journal of Pediatrics. Expert consensus on the diagnosis and treatment of Prader- Willi syndrome in China(2015)., 2015, 53(6): 419–424.

中华医学会儿科学分会内分泌遗传代谢学组, 《中华儿科杂志》编辑委员会. 中国Prader-Willi综合征诊治专家共识(2015). 中华儿科杂志, 2015, 53(6): 419– 424.

[6] Aycan Z, Baş VN. Prader-Willi syndrome and growth hormone deficiency.,2014, 6(2): 62–67.

[7] Butler MG, Theodoro MF, Bittel DC, Donnelly JE. Energy expenditure and physical activity in Prader-Willi syndrome: comparison with obese subjects.,2007, 143A(5): 449–459.

[8] Eiholzer U, Schlumpf M, Nordmann Y, l'Allemand D. Early manifestations of Prader-Willi syndrome: influ­ence of growth hormone.,2001, 14(Suppl 6): 1441–1444.

[9] Eldar-Geva T, Hirsch HJ, Benarroch F, Rubinstein O, Gross-Tsur V. Hypogonadism in females with Prader- Willi syndrome from infancy to adulthood: variable combinations of a primary gonadal defect and hypotha­lamic dysfunction.,2010, 162(2): 377–384.

[10] Myers SE, Carrel AL, Whitman BY, Allen DB. Sustained benefit after 2 years of growth hormone on body composition, fat utilization, physical strength and agility, and growth in Prader-Willi syndrome.,2000, 137(1): 42–49.

[11] Butler MG. Prader-Willi syndrome: current understan­ding of cause and diagnosis.,1990, 35(3): 319–332.

[12] Miller JL, Lynn CH, Driscoll DC, Goldstone AP, Gold JA, Kimonis V, Dykens E, Butler MG, Shuster JJ, Driscoll DJ. Nutritional phases in Prader-Willi syndrome.,2011, 155A(5): 1040–1049.

[13] Butler MG, Manzardo AM, Heinemann J, Loker C, Loker J. Causes of death in Prader-Willi syndrome: Prader-Willi Syndrome Association (USA) 40-year mortality survey., 2017, 19(6): 635–642.

[14] Heymsfield SB, Avena NM, Baier L, Brantley P, Bray GA, Burnett LC, Butler MG, Driscoll DJ, Egli D, Elmquist J, Forster JL, Goldstone AP, Gourash LM, Greenway FL, Han JC, Kane JG, Leibel RL, Loos RJF, Scheimann AO, Roth CL, Seeley RJ, Sheffield V, Tauber M, Vaisse C, Wang LH, Waterland RA, Wevrick R, Yanovski JA, Zinn AR. Hyperphagia: current concepts and future directions proceedings of the 2nd international conference on hyperphagia.,2014, 22 (Suppl 1): S1–S17.

[15] Crinò A, Fintini D, Bocchini S, Grugni G. Obesity management in Prader-Willi syndrome: current per­spectives.,2018, 11: 579–593.

[16] Tan QM, Orsso CE, Deehan EC, Triador L, Field CJ, Tun HM, Han JC, Müller TD, Haqq AM. Current and emerging therapies for managing hyperphagia and obesity in Prader-Willi syndrome: A narrative review.,2020, 21(5): e12992.

[17] Vogels A, Moerman P, Frijns JP, Bogaert GA. Testicular histology in boys with Prader-Willi syndrome: fertile or infertile?,2008, 180(4 Suppl): 1800–1804.

[18] Bakker NE, Wolffenbuttel KP, Looijenga LHJ, Hokken- Koelega ACS. Testes in infants with Prader-Willi syndrome: human chorionic gonadotropin treatment, surgery and histology.,2015, 193(1): 291–298.

[19] Zitzmann M, Nieschlag E. Hormone substitution in male hypogonadism.,2000, 161(1–2): 73–88.

[20] Beebe DW. Neurobehavioral morbidity associated with disordered breathing during sleep in children: a comprehensive review.,2006, 29(9): 1115–1134.

[21] Sedky K, Bennett DS, Pumariega A. Prader Willi syndrome and obstructive sleep apnea: co-occurrence in the pediatric population.,2014, 10(4): 403–409.

[22] Bittel DC, Kibiryeva N, Sell SM, Strong TV, Butler MG. Whole genome microarray analysis of gene expression in Prader-Willi syndrome.,2007, 143A(5): 430–442.

[23] Fronczek R, Lammers GJ, Balesar R, Unmehopa UA, Swaab DF. The number of hypothalamic hypocretin (orexin) neurons is not affected in Prader-Willi syndrome.,2005, 90(9): 5466–5470.

[24] Aran A, Einen M, Lin L, Plazzi G, Nishino S, Mignot E. Clinical and therapeutic aspects of childhood narcolepsy- cataplexy: a retrospective study of 51 children.,2010, 33(11): 1457–1464.

[25] Meyer SL, Splaingard M, Repaske DR, Zipf W, Atkins J, Jatana K. Outcomes of adenotonsillectomy in patients with Prader-Willi syndrome.,2012, 138(11): 1047–1051.

[26] Whittington J, Holland A, Webb T, Butler J, Clarke D, Boer H. Academic underachievement by people with Prader-Willi syndrome.,2004, 48(Pt 2): 188–200.

[27] Cassidy SB, Schwartz S, Miller JL, Driscoll DJ. Prader-Willi syndrome.,2012, 14(1): 10–26.

[28] Böhm B, Ritzén EM, Lindgren AC. Growth hormone treatment improves vitality and behavioural issues in children with Prader-Willi syndrome.,2015, 104(1): 59–67.

[29] Deal CL, Tony M, Höybye C, Allen DB, Tauber M, Christiansen JS, 2011 Growth Hormone in Prader-Willi Syndrome Clinical Care Guidelines Workshop Partici­pants. GrowthHormone Research Society workshop summary: consensus guidelines for recombinant human growth hormone therapy in Prader-Willi syndrome.,2013, 98(6): E1072–E1087.

[30] Butler MG. Prader-Willi syndrome: obesity due to genomic imprinting.,2011, 12(3): 204– 215.

[31] Bittel DC, Kibiryeva N, Butler MG. Expression of 4 genes between chromosome 15 breakpoints 1 and 2 and behavioral outcomes in Prader-Willi syndrome.,2006, 118(4): e1276–e1283.

[32] Butler MG, Bittel DC, Kibiryeva N, Talebizadeh Z, Thompson T. Behavioral differences among subjects with Prader-Willi syndrome and type I or type II deletion and maternal disomy.,2004, 113(3 Pt 1): 565–573.

[33] Zarcone J, Napolitano D, Peterson C, Breidbord J, Ferraioli S, Caruso-Anderson M, Holsen L, Butler MG, Thompson T. The relationship between compulsive behaviour and academic achievement across the three genetic subtypes of Prader-Willi syndrome.,2007, 51(Pt. 6): 478–487.

[34] Burnside RD, Pasion R, Mikhail FM, Carroll AJ, Robin NH, Youngs EL, Gadi IK, Keitges E, Jaswaney VL, Papenhausen PR, Potluri VR, Risheg H, Rush B, Smith JL, Schwartz S, Tepperberg JH, Butler MG. Microdeletion/microduplication of proximal 15q11.2 between BP1 and BP2: a susceptibility region for neurological dysfunction including developmental and language delay.,2011, 130(4): 517–528.

[35] Butler MG. Clinical and genetic aspects of the 15q11.2 BP1-BP2 microdeletion disorder.,2017, 61(6): 568–579.

[36] Chang X, Qu HQ, Liu YC, Glessner J, Hou CP, Wang FX, Li J, Sleiman P, Hakonarson H. Microduplications at the 15q11.2 BP1-BP2 locus are enriched in patients with anorexia nervosa.,2019, 113: 34–38.

[37] Chen H, Victor AK, Klein J, Tacer KF, Tai DJ, de Esch C, Nuttle A, Temirov J, Burnett LC, Rosenbaum M, Zhang YY, Ding L, Moresco JJ, Diedrich JK, Yates JR, Tillman HS, Leibel RL, Talkowski ME, Billadeau DD, Reiter LT, Potts PR. Loss of MAGEL2 in Prader-Willi syndrome leads to decreased secretory granule and neuropeptide production., 2020, 5(17): e138576.

[38] Goytain A, Hines RM, El-Husseini A, Quamme GA. NIPA1(SPG6), the basis for autosomal dominant form of hereditary spastic paraplegia, encodes a functional Mg2+ transporter.,2007, 282(11): 8060– 8068.

[39] Goytain A, Hines RM, Quamme GA. Functional characterization of NIPA2, a selective Mg2+ transporter.,2008, 295(4): C944–C953.

[40] Liu NN, Xie H, Xiang-Wei WS, Gao K, Wang TS, Jiang YW. The absence of NIPA2 enhances neural excitability through BK (big potassium) channels.,2019, 25(8): 865–875.

[41] Zhao W, Zhang WL, Ma HD, Yang MW. NIPA2 regulates osteoblast function by modulating mitophagy in type 2 diabetes osteoporosis.,2020, 10(1): 3078.

[42] Karsenty G. Leptin controls bone formation through a hypothalamic relay.,2001, 56: 401–415.

[43] Murphy SM, Preble AM, Patel UK, O'Connell KL, Dias DP, Moritz M, Agard D, Stults JT, Stearns T. GCP5 and GCP6: two new members of the human gamma-tubulin complex.,2001, 12(11): 3340–3352.

[44] Maver A, Čuturilo G, Kovanda A, Miletić A, Peterlin B. Rare missense TUBGCP5 gene variant in a patient with primary microcephaly.,2019, 62(12): 103598.

[45] De Wolf V, Brison N, Devriendt K, Peeters H. Genetic counseling for susceptibility loci and neurodevelop­mental disorders: the del15q11.2 as an example.,2013, 161A(11): 2846–2854.

[46] Nowicki ST, Tassone F, Ono MY, Ferranti J, Croquette MF, Goodlin-Jones B, Hagerman RJ. The Prader-Willi phenotype of fragile X syndrome.,2007, 28(2): 133–138.

[47] Babbs RK, Beierle JA, Ruan QT, Kelliher JC, Chen MM, Feng AX, Kirkpatrick SL, Benitez FA, Rodriguez FA, Pierre JJ, Anandakumar J, Kumar V, Mulligan MK, Bryant CD. Cyfip1 haploinsufficiency increases compulsive-like behavior and modulates palatable food intake in mice: dependence on cyfip2 genetic back­ground, parent-of origin, and sex.,2019, 9(9): 3009–3022.

[48] Chen ZC, Borek D, Padrick SB, Gomez TS, Metlagel Z, Ismail AM, Umetani J, Billadeau DD, Otwinowski Z, Rosen MK. Structure and control of the actin regulatory WAVE complex.,2010, 468(7323): 533–538.

[49] Hsiao K, Harony-Nicolas H, Buxbaum JD, Bozdagi- Gunal O, Benson DL. Cyfip1 regulates presynaptic activity during development.,2016, 36(5): 1564–1576.

[50] Zuchero JB, Fu MM, Sloan SA, Ibrahim A, Olson A, Zaremba A, Dugas JC, Wienbar S, Caprariello AV, Kantor C, Leonoudakis D, Lariosa-Willingham K, Kronenberg G, Gertz K, Soderling SH, Miller RH, Barres BA. CNS myelin wrapping is driven by actin disassembly.,2015, 34(2): 152–167.

[51] Verkerk AJ, Pieretti M, Sutcliffe JS, Fu YH, Kuhl DP, Pizzuti A, Reiner O, Richards S, Victoria MF, Zhang FP, Eussen BE, van Ommen GJB, Blonden LA, Riggins GJ, Chastain JL, Kunst CB, Galjaard H, Caskey CT, Nelson DL, Oostra BA, Warren ST. Identification of a gene (FMR-1) containing a CGG repeat coincident with a breakpoint cluster region exhibiting length variation in fragile X syndrome., 1991, 65(5): 905–914.

[52] Napoli I, Mercaldo V, Boyl PP, Eleuteri B, Zalfa F, De Rubeis S, Di Marino D, Mohr E, Massimi M, Falconi M, Witke W, Costa-Mattioli M, Sonenberg N, Achsel T, Bagni C. The fragile X syndrome protein represses activity-dependent translation through CYFIP1, a new 4E-BP.,2008, 134(6): 1042–1054.

[53] Conn CS, Yang HJ, Tom HJ, Ikeda K, Oses-Prieto JA, Vu H, Oguri Y, Nair S, Gill RM, Kajimura S, DeBerardinis RJ, Burlingame AL, Ruggero D. The major cap-binding protein eIF4E regulates lipid homeostasis and diet-induced obesity.,2021, 3(2): 244–257.

[54] Abreu AP, Toro CA, Song YB, Navarro VM, Bosch MA, Eren A, Liang JN, Carroll RS, Latronico AC, Rønnekleiv OK, Aylwin CF, Lomniczi A, Ojeda S, Kaiser UB. MKRN3 inhibits the reproductive axis through actions in kisspeptin-expressing neurons.,2020, 130(8): 4486–4500.

[55] Macedo DB, Abreu AP, Reis ACS, Montenegro LR, Dauber A, Beneduzzi D, Cukier P, Silveira LFG, Teles MG, Carroll RS, Junior GG, Filho GG, Gucev Z, Arnhold IJP, de Castro M, Moreira AC, Martinelli CE, Hirschhorn JN, Mendonca BB, Brito VN, Antonini SR, Kaiser UB, Latronico AC. Central precocious puberty that appears to be sporadic caused by paternally inherited mutations in the imprinted gene makorin ring finger 3.,2014, 99(6): E1097–E1103.

[56] Abreu AP, Dauber A, Macedo DB, Noel SD, Brito VN, Gill JC, Cukier P, Thompson IR, Navarro VM, Gagliardi PC, Rodrigues T, Kochi C, Longui CA, Beckers D, de Zegher F, Montenegro LR, Mendonca BB, Carroll RS, Hirschhorn JN, Latronico AC, Kaiser UB. Central precocious puberty caused by mutations in the imprinted gene MKRN3.,2013, 368(26): 2467– 2475.

[57] Crinò A, Di Giorgio G, Schiaffini R, Fierabracci A, Spera S, Maggioni A, Gattinara GC. Central precocious puberty and growth hormone deficiency in a boy with Prader-Willi syndrome.,2008, 167(12): 1455–1458.

[58] Ludwig NG, Radaeli RF, Silva MMX, Romero CM, Carrilho AJF, Bessa D, Macedo DB, Oliveira ML, Latronico AC, Mazzuco TL. A boy with Prader-Willi syndrome: unmasking precocious puberty during growth hormone replacement therapy.,2016, 60(6): 596–600.

[59] Barreiro ML, Tena-Sempere M. Ghrelin and reproduc­tion: a novel signal linking energy status and fertility?,2004, 226(1–2): 1–9.

[60] Bischof JM, Stewart CL, Wevrick R. Inactivation of the mouse Magel2 gene results in growth abnormalities similar to Prader-Willi syndrome.,2007, 16(22): 2713–2719.

[61] Buiting K, Di Donato N, Beygo J, Bens S, von der Hagen M, Hackmann K, Horsthemke B. Clinical phenotypes of MAGEL2 mutations and deletions., 2014, 9: 40.

[62] Schaaf CP, Gonzalez-Garay ML, Xia F, Potocki L, Gripp KW, Zhang BL, Peters BA, McElwain MA, Drmanac R, Beaudet AL, Caskey CT, Yang YP. Truncating mutations of MAGEL2 cause Prader-Willi phenotypes and autism.,2013, 45(11): 1405–1408.

[63] Tacer KF, Potts PR. Cellular and disease functions of the Prader-Willi Syndrome gene MAGEL2.,2017, 474(13): 2177–2190.

[64] Broberger C, Johansen J, Johansson C, Schalling M, Hökfelt T. The neuropeptide Y/agouti gene-related protein (AGRP) brain circuitry in normal, anorectic, and monosodium glutamate-treated mice.,1998, 95(25): 15043–15048.

[65] Cone RD. Anatomy and regulation of the central melanocortin system.,2005, 8(5): 571– 578.

[66] Hao YH, Doyle JM, Ramanathan S, Gomez TS, Jia D, Xu M, Chen ZJ, Billadeau DD, Rosen MK, Potts PR. Regulation of WASH-dependent actin polymerization and protein trafficking by ubiquitination.,2013, 152(5): 1051–1064.

[67] Maillard J, Park S, Croizier S, Vanacker C, Cook JH, Prevot V, Tauber M, Bouret SG. Loss of Magel2 impairs the development of hypothalamic Anorexigenic circuits.,2016, 25(15): 3208–3215.

[68] Swaab DF, Purba JS, Hofman MA. Alterations in the hypothalamic paraventricular nucleus and its oxytocin neurons (putative satiety cells) in Prader-Willi syndrome: a study of five cases.,1995, 80(2): 573–579.

[69] Ates T, Oncul M, Dilsiz P, Topcu IC, Civas CC, Alp MI, Aklan I, Ates Oz E, Yavuz Y, Yilmaz B, Sayar Atasoy N, Atasoy D. Inactivation of Magel2 suppresses oxytocin neurons through synaptic excitation-inhibition imbalance.,2019, 121: 58–64.

[70] Grinevich V, Knobloch-Bollmann HS, Eliava M, Busnelli M, Chini B. Assembling the puzzle: pathways of oxytocin signaling in the brain.,2016, 79(3): 155–164.

[71] Schaller F, Watrin F, Sturny R, Massacrier A, Szepetowski P, Muscatelli F. A single postnatal injection of oxytocin rescues the lethal feeding behaviour in mouse newborns deficient for the imprinted Magel2 gene.,2010, 19(24): 4895–4905.

[72] Hao YH, Fountain MD, Fon Tacer K, Xia F, Bi WM, Kang SHL, Patel A, Rosenfeld JA, Le Caignec C, Isidor B, Krantz ID, Noon SE, Pfotenhauer JP, Morgan TM, Moran R, Pedersen RC, Saenz MS, Schaaf CP, Potts PR. Usp7 acts as a molecular rheostat to promote WASH- dependent endosomal protein recycling and is mutated in a human neurodevelopmental disorder.,2015, 59(6): 956–969.

[73] Kozlov SV, Bogenpohl JW, Howell MP, Wevrick R, Panda S, Hogenesch JB, Muglia LJ, Van Gelder RN, Herzog ED, Stewart CL. The imprinted gene Magel2 regulates normal circadian output.,2007, 39(10): 1266–1272.

[74] Mercer RE, Wevrick R. Loss of magel2, a candidate gene for features of Prader-Willi syndrome, impairs reproductive function in mice.,2009, 4(1): e4291.

[75] Kobayashi M, Taniura H, Yoshikawa K. Ectopic expression of necdin induces differentiation of mouse neuroblastoma cells.,2002, 277(44): 42128–42135.

[76] Taniura H, Taniguchi N, Hara M, Yoshikawa K. Necdin, a postmitotic neuron-specific growth suppressor, interacts with viral transforming proteins and cellular transcription factor E2F1.,1998, 273(2): 720–728.

[77] Uetsuki T, Takagi K, Sugiura H, Yoshikawa K. Structure and expression of the mouse necdin gene. Identification of a postmitotic neuron-restrictive core promoter.,1996, 271(2): 918–924.

[78] Taniura H, Matsumoto K, Yoshikawa K. Physical and functional interactions of neuronal growth suppressor necdin with p53.,1999, 274(23): 16242– 16248.

[79] Gérard M, Hernandez L, Wevrick R, Stewart CL. Disruption of the mouse necdin gene results in early post-natal lethality.,1999, 23(2): 199–202.

[80] Andrieu D, Watrin F, Niinobe M, Yoshikawa K, Muscatelli F, Fernandez PA. Expression of the Prader-Willi gene Necdin during mouse nervous system development correlates with neuronal differentiation and p75NTR expression.,2003, 3(6): 761–765.

[81] Matarazzo V, Caccialupi L, Schaller F, Shvarev Y, Kourdougli N, Bertoni A, Menuet C, Voituron N, Deneris E, Gaspar P, Bezin L, Durbec P, Hilaire G, Muscatelli F. Necdin shapes serotonergic development and SERT activity modulating breathing in a mouse model for Prader-Willi syndrome.,2017, 6: e32640.

[82] Lee S, Walker CL, Karten B, Kuny SL, Tennese AA, O'Neill MA, Wevrick R. Essential role for the Prader- Willi syndrome protein necdin in axonal outgrowth.,2005, 14(5): 627–637.

[83] Pagliardini S, Ren J, Wevrick R, Greer JJ. Develop­mental abnormalities of neuronal structure and function in prenatal mice lacking the prader-willi syndrome gene necdin.,2005, 167(1): 175–191.

[84] Muscatelli F, Abrous DN, Massacrier A, Boccaccio I, Le Moal M, Cau P, Cremer H. Disruption of the mouse Necdin gene results in hypothalamic and behavioral alterations reminiscent of the human Prader-Willi syndrome.,2000, 9(20): 3101–3110.

[85] Swaab DF. Prader-Willi syndrome and the hypothalamus.,1997, 423: 50-54.

[86] Takazaki R, Nishimura I, Yoshikawa K. Necdin is required for terminal differentiation and survival of primary dorsal root ganglion neurons.,2002, 277(2): 220–232.

[87] Lu RB, Dong YF, Li JD. Necdin regulates BMAL1 stability and circadian clock through SGT1-HSP90 chaperone machinery.,2020, 48(14): 7944–7957.

[88] Hogenboom R, Kalsbeek MJ, Korpel NL, de Goede P, Koenen M, Buijs RM, Romijn JA, Swaab DF, Kalsbeek A, Yi CX. Loss of arginine vasopressin- and vasoactive intestinal polypeptide-containing neurons and glial cells in the suprachiasmatic nucleus of individuals with type 2 diabetes.,2019, 62(11): 2088–2093.

[89] Bratkovič T, Božič J, Rogelj B. Functional diversity of small nucleolar RNAs.,2020, 48(4): 1627–1651.

[90] de Smith AJ, Purmann C, Walters RG, Ellis RJ, Holder SE, Van Haelst MM, Brady AF, Fairbrother UL, Dattani M, Keogh JM, Henning E, Yeo GSH, O'Rahilly S, Froguel P, Farooqi IS, Blakemore AIF. A deletion of the HBII-85 class of small nucleolar RNAs (snoRNAs) is associated with hyperphagia, obesity and hypogonadism.,2009, 18(17): 3257–3265.

[91] Lassi G, Maggi S, Balzani E, Cosentini I, Garcia-Garcia C, Tucci V. Working-for-food behaviors: a preclinical study in Prader-Willi mutant mice.,2016, 204(3): 1129–1138.

[92] Polex-Wolf J, Lam BY, Larder R, Tadross J, Rimmington D, Bosch F, Cenzano VJ, Ayuso E, Ma MK, Rainbow K, Coll AP, O'Rahilly S, Yeo GS. Hypothalamic loss of Snord116 recapitulates the hyperphagia of Prader-Willi syndrome.,2018, 128(3): 960–969.

[93] Qi Y, Purtell L, Fu M, Lee NJ, Aepler J, Zhang L, Loh K, Enriquez RF, Baldock PA, Zolotukhin S, Campbell LV, Herzog H. Snord116 is critical in the regulation of food intake and body weight.,2016, 6: 18614.

[94] Qi Y, Purtell L, Fu M, Zhang L, Zolotukhin S, Campbell L, Herzog H. Hypothalamus specific re-introduction of SNORD116 into otherwise Snord116 deficient mice increased energy expenditure.,2017, 29(10). doi: 10.1111/jne.12457.

[95] Zhang Q, Bouma GJ, McClellan K, Tobet S. Hypothalamic expression of snoRNA Snord116 is consistent with a link to the hyperphagia and obesity symptoms of Prader-Willi syndrome.,2012, 30(6): 479–485.

[96] Purtell L, Qi Y, Campbell L, Sainsbury A, Herzog H. Adult-onset deletion of the Prader-Willi syndrome susceptibility gene Snord116 in mice results in reduced feeding and increased fat mass.,2017, 6(2): 88–97.

[97] Kufel J, Grzechnik P. Small nucleolar RNAs tell a different tale.,2019, 35(2): 104–117.

[98] Lassi G, Priano L, Maggi S, Garcia-Garcia C, Balzani E, El-Assawy N, Pagani M, Tinarelli F, Giardino D, Mauro A, Peters J, Gozzi A, Grugni G, Tucci V. Deletion of the Snord116/SNORD116 alters sleep in mice and patients with Prader-Willi syndrome.,2016, 39(3): 637– 644.

[99] Resnick JL, Nicholls RD, Wevrick R, Prader-Willi Syndrome Animal Models Working Group. Recom­mendations for the investigation of animal models of Prader-Willi syndrome.,2013, 24(5–6): 165–178.

[100] Schöne C, Burdakov D. Orexin/hypocretin and organizing principles for a diversity of wake-promoting neurons in the brain.,2017, 33: 51–74.

[101] Chemelli RM, Willie JT, Sinton CM, Elmquist JK, Scammell T, Lee C, Richardson JA, Williams SC, Xiong Y, Kisanuki Y, Fitch TE, Nakazato M, Hammer RE, Saper CB, Yanagisawa M. Narcolepsy in orexin knockout mice: molecular genetics of sleep regulation.,1999, 98(4): 437–451.

[102] Coulson RL, Yasui DH, Dunaway KW, Laufer BI, Vogel Ciernia A, Zhu YH, Mordaunt CE, Totah TS, LaSalle JM. Snord116-dependent diurnal rhythm of DNA methylation in mouse cortex.,2018, 9(1): 1616.

[103] Krauchi K, Deboer T. The interrelationship between sleep regulation and thermoregulation.,2010, 15(2): 604–625.

[104] Cerri M, Del Vecchio F, Mastrotto M, Luppi M, Martelli D, Perez E, Tupone D, Zamboni G, Amici R. Enhanced slow-wave EEG activity and thermoregulatory impair­ment following the inhibition of the lateral hypotha­lamus in the rat.,2014, 9(11): e112849.

[105] Kuwaki T. Thermoregulation under pressure: a role for orexin neurons.,2015, 2(3): 379–391.

[106] Butler MG. Hypopigmentation: a common feature of Prader-Labhart-Willi syndrome.,1989, 45(1): 140–146.

[107] Ji Y, Rebert NA, Joslin JM, Higgins MJ, Schultz RA, Nicholls RD. Structure of the highly conserved HERC2 gene and of multiple partially duplicated paralogs in human.,2000, 10(3): 319–329.

[108] Ji Y, Walkowicz MJ, Buiting K, Johnson DK, Tarvin RE, Rinchik EM, Horsthemke B, Stubbs L, Nicholls RD. The ancestral gene for transcribed, low-copy repeats in the Prader-Willi/Angelman region encodes a large protein implicated in protein trafficking, which is deficient in mice with neuromuscular and spermiogenic abnormalities.,1999, 8(3): 533–542.

[109] Baxter LR, Saxena S, Brody AL, Ackermann RF, Colgan M, Schwartz JM, Allen-Martinez Z, Fuster JM, Phelps ME. Brain mediation of obsessive-compulsive disorder symptoms: evidence from functional brain imaging studies in the human and nonhuman primate.,1996, 1(1): 32–47.

[110] Berninger B, Marty S, Zafra F, da Penha Berzaghi M, Thoenen H, Lindholm D. GABAergic stimulation switches from enhancing to repressing BDNF expres­sion in rat hippocampal neurons during maturation in vitro.,1995, 121(8): 2327–2335.

[111] Horvath TL, Bechmann I, Naftolin F, Kalra SP, Leranth C. Heterogeneity in the neuropeptide Y-containing neurons of the rat arcuate nucleus: GABAergic and non-GABAergic subpopulations.,1997, 756(1–2): 283–286.

[112] Kim Y, Lee HM, Xiong Y, Sciaky N, Hulbert SW, Cao XY, Everitt JI, Jin J, Roth BL, Jiang YH. Targeting the histone methyltransferase G9a activates imprinted genes and improves survival of a mouse model of Prader-Willi syndrome.,2017, 23(2): 213–222.

[113] Kim Y, Wang SE, Jiang YH. Epigenetic therapy of Prader-Willi syndrome.,2019, 208: 105–118.

[114] Huang WK, Wong SZH, Pather SR, Nguyen PTT, Zhang F, Zhang DY, Zhang ZJ, Lu L, Fang WQ, Chen LY, Fernandes A, Su YJ, Song HJ, Ming GL. Generation of hypothalamic arcuate organoids from human induced pluripotent stem cells., 2021, 28(9): 1657–1670.e10.

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

国家自然科学基金项目(编号：81873654)资助[Supported by the National Natural Science Foundation of China (No. 81873654)]

王心缘，在读硕士研究生，专业方向：药理学。E-mail: darlingxyxy@163.com

高原青，博士，教授，研究方向：神经药理。E-mail: yuanqinggao@njmu.edu.cn

10.16288/j.yczz.22-188

(责任编委: 孟卓贤)