癫痫遗传学及表观遗传学研究进展_《癫痫杂志》

作者：

 胡子英 ¹ , 王红艳 ² ,  王艺 ¹

1. 复旦大学附属儿科医院(上海, 200032);
2. 复旦大学生命科学院(上海, 200032);

关键词：

癫痫遗传学研究

DOI：

10.7507/2096-0247.20160091

视频：

导出 下载 收藏 扫码 引用

摘要 全文 图表 视频 参考文献 施引文献 补充材料

癫痫是一种以反复发作的痉挛为特点的严重的神经系统疾病。它是由多种原因导致的,主要有遗传因素、脑损伤及环境因素,但是具体发病机制还不清楚。遗传性癫痫家族研究发现癫痫是由一些编码离子通道以及神经递质受体蛋白的基因突变导致的。随着技术进步和研究深入,逐渐发现癫痫遗传不仅由离子通道和神经递质基因控制,还受突触小泡转运通路,染色质重塑和转录,mTOR蛋白信号通路等相关基因,染色体拷贝数变异及表观遗传学的影响。该文主要讨论癫痫相关基因、染色体异常和表观遗传学对癫痫发生的影响。

引用本文： 胡子英, 王红艳, 王艺. 癫痫遗传学及表观遗传学研究进展. 癫痫杂志, 2016, 2(6): 515-522. doi: 10.7507/2096-0247.20160091 复制

癫痫是一种常见的神经系统疾病，是由于中枢神经系统异常放电导致的经常复发的不自主的痉挛。癫痫影响着世界将近3%的人，其发病机理还不清楚，被认为有：创伤、病毒感染、获得性脑损伤、代谢变异、先天脑畸形等^[1]，在对癫痫遗传家族的研究中发现癫痫主要还受遗传因素的控制。

1 癫痫与遗传学的关系

自从1995年发现的第一个单基因突变开始，遗传因素就在癫痫的发生机制中承担着至关重要的角色。然而，尽管导致癫痫的原因多种多样并具有基因异质性，癫痫已经被认为是一个高遗传的疾病^{[2, 3]}。流行病学关于癫痫家族和双胞胎的研究为遗传性癫痫提供了证据^[4-8]。例如，一类先天性全身性癫痫病患者的第一代亲属的患病概率是8%～12%，而普通人的患病概率仅约0.5%^[4]。自1980年遗传学在癫痫病中重要地位被报道之后，对于致力于癫痫家族的致病原因和癫痫动物模型关于遗传的重要作用研究有了强大的证据^[5]。离子通道基因的鉴定也成为癫痫遗传学研究的主要方面，但是在小鼠模型的癫痫遗传学研究中，仅有1/4归因于通道相关基因的病变^[6]。最近的研究通过对大量癫痫患者全外显子组或全基因组测序也发现除了离子通道相关基因外，多重通路相关基因突变也会导致癫痫发生，目前发现的主要有突触小泡转运通路，染色质重塑和转录，mTOR蛋白信号通路等。

1.1 离子通道和神经递质受体基因对癫痫的影响

由于癫痫发生是由神经系统异常放电所致，所以研究者们首先基于神经系统对癫痫的发病机理进行研究。目前多项研究证实很多人类特发性癫痫是“离子通道病”^[7],即编码离子通道的基因发生突变，翻译的离子通道蛋白有缺陷而致病。主要包括电压门控离子通道(K⁺,Na⁺,Ca²⁺,Cl^-和HCN)和受体门控离子通道(乙酰胆碱和GABA受体)。近十多年的研究中，研究者们发现很多编码离子通道的基因与自发性癫痫相关。

良性家族性新生儿惊厥(Benign familial neonatal infantile seizures,BFNIS)是一种罕见的原发性全身性癫痫，是常染色体显性遗传。研究发现，BFNIS是由电压门控钾离子通道基因KCNQ2和KCNQ3突变所致^{[8, 9]}。伴热性惊厥的全身性癫痫(Generalized epilepsy with febrile seizures plus,GEFS+)也是一种常染色体显性遗传的原发性全身性癫痫，主要表现为婴儿期伴热惊厥，6岁以后无热惊厥，青春期后将不再发病。在对GEFS+家族的研究中，鉴定出3个钠离子通道亚基因(SCN1B,SCN1A,和 SCN2A)突变和2个GABA受体亚基因(GABRG2和GABRD)突变^[10-14]，其中SCN1A的突变还与严重的婴儿肌痉挛性癫痫(severe myoclonic epilepsy of infancy,SMEI)相关^{[15, 16]}。而BFNIS,GEFS+和SMEI患者中鉴定出SCN2A有超过20个突变位点，并且多数突变与BFNIS相关。2012年首次发现另外一个钠离子通道基因SCN8A突变也会导致严重的癫痫脑病^[17]，大部分具有SCN8A突变的癫痫患儿具有相似的临床特征：5个月时开始癫痫发作并伴随发育迟缓和智力低下^[18-21]。最近研究者们通过对3个家系中16例患儿研究发现SCN8A突变也会导致婴儿痉挛和阵发性运动障碍^[22]。

常染色体显性夜发性额叶癫痫(Autosomal dominant nocturnal frontal lobe epilepsy,ADNFLE)为常染色体显性遗传的原发性部分癫痫，外显率为75%。发病年龄不等，儿童期和成年期均有可能发病。研究发现乙酰胆碱受体基因CHRNA4和CHRNB2突变将导致ADNFLE发生^[23]。据报道，GABA受体亚基因(GANRA1、GABRB3、GABRG2和GABRD)与遗传性癫痫综合征包括儿童失神癫痫(Childhood absence epilepsy,CAE)、青少年肌阵挛性癫痫(JME)、高热惊厥(FS)、GEFS+和SMEI具有相关性^[24-30]。2004年，Chen Y等首次在汉族人群中鉴定出与CAE相关的12个稀有杂合错义突变^[31]。到目前为止，已经鉴定出在基因CACNA1H上有超过30个突变位点与特发性全身性癫痫(Idiopathic generalized epilepsy,IGE)相关^[32]。但是进一步的研究证明，CACNA1H的突变虽然能导致CAE、青少年失神癫痫(JAE)、JME、FS和颞叶癫痫(TLE)的易感性，但是还不足以说明它们的发病机理^[27-32]。CLCN2基因编码电压门控氯离子通道蛋白，它的突变也会影响包括CAE、JAE、JME和清醒中癫痫大发作这4类常见的特发性全身性癫痫^[33]。CLCN4编码2Cl^-/H⁺交换器ClC-4，在大脑中显著表达。最近的研究通过对16个家庭中的52个CLCN4相关病例详细分析，揭露CLCN4的突变能够引起X-连锁的癫痫和智力缺陷^[34]。

1.2 突触小泡转运通路基因对癫痫的影响

早期婴儿癫痫脑病爆发抑制(Early infantile epilepsy encephalopathy,EIEE)又称大田原综合征，是一种严重的早期癫痫发作形式，研究证明它的发生与STXBP1基因的突变相关，而STXBP1编码的蛋白还涉及突出小泡的释放^[35]。对于许多癫痫相关状况可能的情况，STXBP1远不止于对EIEE的影响。已经有报道在一个智力缺陷的癫痫病人中STXBP1杂合子突变，这个表征更加证明STXBP1不止针对EIEE^[36]。SCN1A,SCN1B 和 GABRG2已经被鉴定会导致伴随或不伴随癫痫的FS，最近的研究又发现STX1B(编码突触融合蛋白1B)，它的突变会导致FS并伴随癫痫发生^[37]。在动物模型中SNAP25突变会导致焦虑、运动失调和痉挛，在对1例患有全身性癫痫并有智力缺陷的患儿测序发现她也存在原发性SNAP25突变，但是要证明SNAP25突变能够导致癫痫还需要更多的证据^[38]。NECAP1编码网格调节蛋白，研究发现NECAP1的功能缺失可能会导致严重的婴幼儿癫痫脑病^[39]。DNM1编码动力蛋白1，调节突触传导，对突触小泡的释放起重要作用。在对356例孩子患有癫痫脑病、婴儿点头痉挛和Lennox Gastaut综合征的三口之家全外显子测序发现5例患儿具有DNM1原发性突变，统计分析发现DNM1也是癫痫脑病的致病基因^[40]。

1.3 染色质重塑与转录，mTOR信号通路基因对癫痫的影响

CHD2编码的染色质解旋酶DNA结合蛋白2，是一个染色质重塑因子。到今天为止，已经鉴定出超过20例癫痫患者具有CHD2的突变，并且大部分突变是原发性的^[41-46]。这些癫痫患者大部分表现为多重痉挛大发作、肌痉挛和光敏性^[42]。mTOR是一种非典型丝氨酸/苏氨酸蛋白激酶，可整合细胞外信号，磷酸化下游靶蛋白核糖体激酶，影响基因转录和蛋白翻译，参与调控细胞生长、增殖、生存、运动和新陈代谢。mTOR信号通路失调会导致许多疾病，包括结节状硬化(TSC1，TSC2基因突变)，半侧巨脑畸形(AKT3，PIK3CA,MTOR)和集中性皮质发育不良(DEPDC5，AKT3，MTOR)^{[47, 48]}。mTOR信号通路失调还会导致难治性癫痫，智力缺陷和孤独症。DEPDC5是GATOR复合体的一个成员，对mTOR通路具有负调控作用。两个研究组同时发现DEPDC5突变会导致集中性癫痫^{[49, 50]}。后来的研究还发现DEPDC5突变会增加癫痫中突然致死的风险^[51]。研究发现MTOR基因突变导致Ⅱ型皮质发育不良从而引发难治性癫痫^[52]。

1.4 其他功能基因对癫痫的影响

ARX是一个X-连锁基因，它与脑畸形、痉挛和智力障碍相关性很强的一个基因，ARX的突变在West综合征^{[53, 54]}和大田原综合征^{[55, 56]}中检测到脑电图(EEG)高度节律失常和爆发抑制。ARX基因突变还会导致特发性婴儿痉挛、X连锁的肌阵挛癫痫、智力障碍伴癫痫、Partington综合征等不伴畸形痉挛，以及X连锁无脑回或积水性无脑畸形伴生殖器异常、Pround综合征等伴畸形的综合征^[57]。ARX基因突变多见于男性，但是女性病例也有报道，并且女性ARX基因突变还有可能导致焦虑症、抑郁症、精神分裂症、学习障碍的精神疾病^[58]。CDKL5定位于Xp22，是一个传统的Rett综合征类似表型相关的基因，诊断说明CDKL5的突变与小头畸形和婴儿点头式痉挛相关^{[59, 60]}。目前，具有CDKL5突变的癫痫脑病也称为CDKL5相关脑病，Bahi-Buisson等对病例总结发现，CDKL5-相关脑病的发作分为3个阶段：第一阶段为出生后3个月内出现癫痫发作，发作比较频繁但EEG 正常；第二阶段发展为婴儿痉挛，EEG 出现高度失律；第三阶段发展为难治性强直或肌阵挛癫痫^{[61, 62]}。另一个X-连锁基因是PCDH19，它编码的蛋白是细胞黏附蛋白的钙黏素家族成员。PCDH19突变会导致女性癫痫伴精神发育迟滞(Epilepsy andmental retardation limited to females，EFMR)^[63]。随后研究发现，PCDH19突变与Dravet综合征以及现在的多种癫痫相关^[64]。

UFM1(Ubiquitin-fold modifier1)是最近鉴定出来的一个泛素类似蛋白，UBA5是编码UFM1的E1激活酶的基因。UBA5双等位基因的突变可以导致UFM1串联结构的破坏从而导致早发型癫痫脑病^[65]。MBOAT7是一个编码溶血磷脂酰基醇酰基转移酶1(LPIAT1)的基因，Johansen等通过对6个近亲结婚的家庭分析，发现MBOAT7的纯合突变可以导致癫痫伴智力缺陷和孤独症^[66]。FARS2位于6p25.1上，编码线粒体苯丙酰胺tRNA合成酶。临床研究发现FARS2的突变能够导致婴儿早发性癫痫脑病^[67]。TBC1D24是在大脑中大量表达的蛋白，编码连接TBC结构域和TLDc结构域之间的唯一的连接蛋白^[68]。TBC1D24的突变可以导致严重的早发型癫痫伴随智力缺陷^[69-75]、耳聋^[76-79]肌阵挛和小脑萎缩^[80] ，以及DOORS(Deafness,onychodystrophy,osteodystrophy,mental retardation and seizures)综合征^[81]。最近研究证明，skywalker-TBC1D24的一个脂质结合口袋突变影响磷酸肌醇的结合从而导致癫痫^[82]。

2 染色体拷贝数变异对癫痫发生的影响

拷贝数变异(Copy number variants,CNVs)是指1 kb的染色体中的缺失和重复。CNVs是正常基因组变异的重要来源，并且很多变异都有导致疾病的风险。在癫痫遗传学领域中，对大量先天性癫痫患者(不伴有抑郁症、智力缺失和同质异型综合征)关于染色体拷贝数异常的研究已有一些成果。一个北欧的研究小组在对1 234例先天性全身癫痫患者研究时，运用高密度单核苷酸多态性排列技术鉴定出2%的患者具有基因微缺失，主要发生在15q11.2和16p13.11这两个位置^[83]。研究还显示，先天性全身性癫痫患者中还存在15q13.3的微缺失，并且15q13.3的微缺失对癫痫发生有最严重风险^[84]。而15q11.2和16q13.11这两处微缺失还在集中性癫痫和其他类型的癫痫患者中被发现^[85]。最近，一些罕见的位于神经元基因外显子上的缺失被发现，这些基因包括NRXN1^[23]、RBFOX1^[86]和GPHN^[87]，它们的缺失可以增加先天性全身性癫痫的发病风险。位于15q26处的CHD2基因缺失，将导致肌阵挛性、光敏性和发育迟缓性癫痫脑病^{[88, 89]}。最近研究发现，CHD2在15q26.1-q26.2处的缺失也会导致癫痫伴随中等智力缺陷^[90]。SLC6A1是一个GABA受体相关蛋白，负责将突触上的GABA再吸收。在4%的无定向肌阵挛性癫痫病人中发现位于3q25处SLC6A1基因具有微缺失^[91]。

3 癫痫与表观遗传学的关系

表观遗传学是指DNA序列不发生改变，而基因表达却发生可遗传改变，并最终导致表型改变。表观遗传基因组可以迅速的对环境做出反应，是控制基因表达的重要的内在机制^[92]，主要包括DNA甲基化、组蛋白修饰和非编码RNA三种形式。并且由于表观遗传不依赖于DNA序列，所以在细胞分裂和增殖中这种遗传物质不会丢失。表观遗传可以导致基因沉默，越来越多的研究表明，表观遗传学在包括癫痫在内的神经系统疾病中起着重要作用^[93]。最近，基于动物模型和人类大脑组织的研究也揭露，癫痫的发生与表观基因组相关，表观遗传学已经成为癫痫研究的一个新兴领域^[94-97]。目前的镇癫药物对超过30%的癫痫患者不起作用，并对癫痫并发症没有影响，也不能阻止癫痫的发展^[98]。或许我们可以从表观遗传学方面寻求治愈癫痫的新治疗方法。目前对癫痫的表观遗传学研究最多的是DNA甲基化和miRNA，我们将从这两个方面介绍对癫痫发生影响。

3.1 DNA甲基化对癫痫发生的影响

DNA甲基化是指由S-腺苷甲硫氨酸作为甲基供体，在DNA甲基转移酶的催化下，将甲基转移到胞嘧啶5′碳原子上，从而变成5-甲基胞嘧啶。DNA甲基化发生在CpG岛，甲基原子团与胞嘧啶上CG二核苷酸共价结合调控基因序列，阻止基因转录，与基因沉默相关^{[99, 100]}。非甲基化与基因的活化相关，去甲基化则与沉默基因重新激活有关^[101]。尽管DNA甲基化在大脑中比较稳定，但仍是有一小部分是动态的，由神经元活性调节的^{[102, 103]}，而这小部分可能涉及到癫痫的发生。并且，DNA甲基化酶活性的增强和DNA高甲基化都与人类癫痫和实验癫痫有很大的相关性^[104-108]。

最近的证据指出：DNA甲基化在癫痫的发生和发展中起着非常关键的作用。研究发现，精神疾病、神经组织退化和包括癫痫在内的神经系统疾病的患者，大脑中都出现了DNA甲基化的变化^{[104, 109-114]}。关于癫痫发生的甲基化假设说明，痉挛可以导致表观遗传的改变从而加重癫痫发生的条件^[115]。甲基-CPG-结合蛋白MBD1-4，MeCP2和KAISO都与DNA甲基化相关。MeCP2基因在大脑中表达并对大脑的发育和功能起着特别的作用。MeCP2突变会导致Rett综合征^[116]，一类例如智力障碍、痉挛、肌肉张力减退和获得性小头畸形的疾病，是由于MeCP2基因发生突变，导致甲基CpG结合域表达和功能异常引起的^{[117, 118]}。人类颞叶癫痫的研究报道，RELN基因的甲基化变化会导致颗粒细胞分散^[104]。并且颞叶癫痫的海马趾中DNA甲基转移酶1和3a的表达水平增加^[119]。在癫痫实验中也发现DNA甲基转移酶的活性是升高的^[107]。在癫痫实验研究中还发现，Grin2c编码的脑原性神经营养因子和谷氨酸盐受体亚基都有甲基化的改变^[120]。全基因组DNA甲基化分析显示，癫痫急性发作时，基因是低甲基化的^[121]，然而，在癫痫的形成过程中基因是高甲基化的^{[105, 107]}。从低甲基化到高甲基化的转变机制还不清楚，但有可能与甲基转移通路中最初的高活性的脱甲基酶有关^{[109, 122]}。

3.2 miRNA对癫痫发生的影响

MicroRNA(miRNA)是一种研究最多的内源性的小非编码RNA，约有22个核苷酸。miRNA是由较长的初级转录物经过一系列核酸剪切酶加工产生，随后组装进RNA诱导的沉默复合体(RISC)，通过减基互补配对方式识别靶mRNA，并根据互补程度不同指导沉默复合体降解靶mRNA或阻遏靶mRNA翻译。最近的研究揭示了许多与癫痫相关的控制基因表达新的层面，将为癫痫发生和获得性癫痫提供新的治疗靶点^[123]。而miRNA就是其中一个重要的层面。在动物模型和癫痫病人的组织研究中已经发现miRNA在癫痫发生中起着调控作用。miRNA失调可能会促进癫痫发生，调节个体的miRNA能够直接影响大脑兴奋性和颞叶癫痫病理生理学特征^[124-126]。

在对颞叶癫痫病人的研究中，已经不止一次的报道miR-221和miR-222表达下调并且与星形胶质细胞内源性细胞间黏附因子1(ICAM1)的表达相关^[127-131]。由于ICAM1是一个免疫和炎症反应应答蛋白^[132]，所以miRNA可能在癫痫发生中起到促炎症发生的作用。在大鼠模型和癫痫病人脑组织的研究中都发现，miR-146a上调可以控制颞叶癫痫的炎症反应^[133]，因为miR-146a的上调导致前炎性细胞活素下调，这可能是癫痫中的补偿机制。在动物模型和颞叶癫痫患者慢性发病过程的研究中还发现，miR-187出现下调^{[120, 134-137]}。而miR-187的表达可以通过抑制包括肿瘤坏死因子(TNF),白细胞介素(IL)-6和IL-12 P40的前炎性细胞活素产生而抗炎的^{[135, 138]}。MiR-9在颞叶癫痫中表达上调^{[127-129, 136, 137, 139-141]}，通过抑制细胞核因子kappa-B1的转录促进炎症发生^[142]。在未成熟大鼠的持续癫痫状态和儿童颞叶癫痫的研究中发现，miR-155在控制炎症反应的通路中表达上调^[120]。通过对动物模型和手术切除的癫痫病人组织的全基因组miRNA表达分析，在对癫痫发生过程中细胞增殖、分化和迁移以及突触重塑、神经元坏死研究中，还鉴定出其他许多癫痫相关的miRNA，但是大部分miRNA的功能还缺少具体实验的验证。

4 展望

癫痫的病因及发病机制非常复杂，在过去十几年里对癫痫遗传学的研究层出不穷，积累了大量的遗传学数据，鉴定出许多与癫痫相关的基因。但是对于已经鉴定出的基因还不足以解释癫痫的发生机制，所以在以后的研究中需要致力于获得更大量的基因序列从而更深入探索癫痫的发病机理。随着测序技术的进步，二代测序技术、全基因组关联分析(GWAS)和大规模并行测序技术(MPS)的应用为发现癫痫相关的新基因或染色体拷贝数变化提供了技术支持。在遗传学突变检测之后，需要进行突变基因致病机理的研究，研发针对不同发病机制的个性化医疗。目前关于表观遗传学与癫痫关系的研究比较少，对于癫痫的表观遗传学，我们只有少量的数据，包括癫痫是否与特殊的DNA脱甲基化作用、核小体重塑、长链非编码RNA(lncRNA)、RNA编辑以及遗传印记的相关研究还很少。而表观遗传修饰可以在大脑中传递信息、改变神经元活性、影响多种转录因子表达，这对癫痫的发生也起着重要作用。所以对表观遗传学的研究也将有助于更深入的了解癫痫发生机制。目前临床上应用的抗癫痫药物，主要是通过整体上降低神经元兴奋性，从而提升其抑制放电水平来实现对癫痫的控制，这种治疗手段不仅疗效有限，还会对患者的行为能力产生未知的副作用。所以发现大量的致病基因及表观遗传学对癫痫的作用，将有助于癫痫发病机理的研究，从而研发出针对癫痫脑病有效的治疗方法。

1 癫痫与遗传学的关系

1.1 离子通道和神经递质受体基因对癫痫的影响

1.2 突触小泡转运通路基因对癫痫的影响

1.3 染色质重塑与转录，mTOR信号通路基因对癫痫的影响

1.4 其他功能基因对癫痫的影响

2 染色体拷贝数变异对癫痫发生的影响

3 癫痫与表观遗传学的关系

3.1 DNA甲基化对癫痫发生的影响

3.2 miRNA对癫痫发生的影响

4 展望

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癫痫与内分泌激素关系的研究进展
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核磁共振图像后处理技术在癫痫术前评估中的应用

《癫痫杂志》

癫痫遗传学及表观遗传学研究进展

摘要 全文 图表 视频 参考文献 施引文献 补充材料

1 癫痫与遗传学的关系

1.1 离子通道和神经递质受体基因对癫痫的影响

1.2 突触小泡转运通路基因对癫痫的影响

1.3 染色质重塑与转录，mTOR信号通路基因对癫痫的影响

1.4 其他功能基因对癫痫的影响

2 染色体拷贝数变异对癫痫发生的影响

3 癫痫与表观遗传学的关系

3.1 DNA甲基化对癫痫发生的影响

3.2 miRNA对癫痫发生的影响

4 展望

1 癫痫与遗传学的关系

1.1 离子通道和神经递质受体基因对癫痫的影响

1.2 突触小泡转运通路基因对癫痫的影响

1.3 染色质重塑与转录，mTOR信号通路基因对癫痫的影响

1.4 其他功能基因对癫痫的影响

2 染色体拷贝数变异对癫痫发生的影响

3 癫痫与表观遗传学的关系

3.1 DNA甲基化对癫痫发生的影响

3.2 miRNA对癫痫发生的影响

4 展望

上一篇

下一篇

Format

Content

《癫痫杂志》

癫痫遗传学及表观遗传学研究进展

摘要 全文 图表 视频 参考文献 施引文献 补充材料

1 癫痫与遗传学的关系

1.1 离子通道和神经递质受体基因对癫痫的影响

1.2 突触小泡转运通路基因对癫痫的影响

1.3 染色质重塑与转录，mTOR信号通路基因对癫痫的影响

1.4 其他功能基因对癫痫的影响

2 染色体拷贝数变异对癫痫发生的影响

3 癫痫与表观遗传学的关系

3.1 DNA甲基化对癫痫发生的影响

3.2 miRNA对癫痫发生的影响

4 展望

1 癫痫与遗传学的关系

1.1 离子通道和神经递质受体基因对癫痫的影响

1.2 突触小泡转运通路基因对癫痫的影响

1.3 染色质重塑与转录，mTOR信号通路基因对癫痫的影响

1.4 其他功能基因对癫痫的影响

2 染色体拷贝数变异对癫痫发生的影响

3 癫痫与表观遗传学的关系

3.1 DNA甲基化对癫痫发生的影响

3.2 miRNA对癫痫发生的影响

4 展望

上一篇

下一篇

Format

Content

摘要全文图表视频参考文献施引文献补充材料