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FRMD7基因所致X连锁特发性先天性眼球震颤的研究进展

Research progress on X-linked idiopathic congenital nystagmus caused by FRMD7 gene

来源期刊： 眼科学报 | 2022年7月 第37卷 第7期： 563-570 发布时间： 收稿时间：2022/12/15 11:24:07 阅读量：4181
作者：
段文华,
胡敏,
关键词：
特发性先天性眼球震颤先天性运动型眼球震颤特发性婴幼儿眼球震颤X连锁FRMD7遗传学
idiopathic congenital nystagmus congenital motor nystagmus idiopathic infantile nystagmus X-linked FRMD7 genetics
DOI：
10.3978/j.issn.1000-4432.2022.06.06
特发性先天性眼球震颤(idiopathic congenital nystagmus，ICN)是一种常见的眼科疾病，患者常有明显的特征性的眼部异常，多伴有学习、社交障碍，对其身心健康影响较大。ICN遗传倾向明显，多表现为X染色体连锁(显性或隐性)，目前研究发现以FRMD7基因突变致病较为显著。近10余年来，国内外学者们在遗传学方面针对ICN和FRMD7基因做了大量的研究工作，取得了令人瞩目的结果。本文就2006年以来研究者们在FRMD7基因所致X连锁ICN的突变类型及位点作一总结，归纳并探讨FRMD7突变可能的致病机制，旨在为学者们提供以往研究结果的查证和未来研究方向的参考。
Idiopathic congenital nystagmus (ICN) is a common ophthalmic disease in which patients often have obvious and characteristic eye abnormalities. ICN patients are often accompanied by learning and social disorders, have a great impact on their physical and mental health. ICN which has an obvious genetic tendency and is mostly manifested as X chromosome linkage (dominant or recessive). Current studies have found that the mutation of FRMD7 gene is the most significant pathogenic factor. In the past 10 years, researchers have done a lot of work on the genetics of ICN and FRMD7 gene, and achieved remarkable results. This review summarizes the typ mutations caused by FRMD7 gene since 2006, and also discusses the possible pathogenesis of FRMD7 mutations, aiming to provide references for scholars to verify previous research results and future research directions.
    特发性先天性眼球震颤(idiopathic congenital nystagmus，ICN)又称为先天性运动型眼球震颤 (congenital motor nystagmus，CMN)或者特发性婴幼儿眼球震颤(idiopathic infantile nystagmus，IIN)，是一种先天性眼球运动障碍性疾病。ICN患
者表现为双眼周期性、不自主性眼震颤，以水平方向为主，通常发生在出生时或出生后6个月内，同时还伴有视力差、歪头视物等特点[1]。ICN不伴有其他眼部及中枢神经系统异常，其病因尚未完全明确，目前研究[2]认为可能是由眼球运动系统本
身的异常发育所致。另一种常见的先天性眼球震颤(congenital nystagmus，CN)类型是感觉缺陷型眼球震颤(sensory defect nystagmus，SDN)。SDN由遗传因素或其他先天性视觉通路病变引起，如先天性白内障、眼白化病、全色盲、先天性无虹膜
症、先天性黄斑发育不良、视皮质发育不良等[3]。
    眼球震颤的患病率估计为24/10 000[4]。此病显著影响视力，许多眼球震颤患者的视觉功能评分低于年龄相关性黄斑变性患者[5]，导致了明显的生活、社交、学习障碍。同时，眼球震颤患者因视力低下和颜面部外观异常(眼球颤动和歪头视物)多伴有不同程度的心理问题[6]，应引起社会各界的关注。CN的遗传模型包括常染色体或X染色体连锁，显性或隐性，其中X染色体连锁遗传和不完全外显率最常见[7]。由于很多先天性眼部疾病均可导致眼球震颤且遗传方式多样、疾病外显率不一，本文仅总结和讨论FRMD7所致X连锁ICN的突变类型及位点，旨在为学者们提供参考及查证。

1 FRMD7 突变致 X 连锁 ICN

    针对ICN家系的分析[8-10]表明X连锁型至少存在3个不同的位点：Xp11.4-p11.3、Xq26-Xq27、Xp22.3-p22.2，但目前研究报道[10-14]以FRMD7(Xq26.2)为主。其他CN的致病基因包括GPR143、TUBB3等，但多属于SND。
    FRMD7是一个蛋白质编码基因，共有12个外显子，编码含714个氨基酸的蛋白质。FRMD7基因在人类胚胎中脑、脊髓、小脑原基、前脑的心室层等组织和器官中均有表达，在发育中的神经视网膜、前庭系统、调节前庭-眼反射的大脑部分表达更为丰富[15-16]。FRMD7编码的蛋白具有一个N '端FERM结构域，该蛋白功能尚不完全清楚，它被认为参与并促进了质膜和细胞骨架之间的信号转导。FRMD7蛋白与FARP1和FARP2蛋白同源，特别是在N端。已有研究[17]表明：FARP1和FARP2参与了神经突的生长和分支，FRMD7蛋白也可能具有类似的功能作用。FRMD7蛋白与钙/钙调蛋白依赖性丝氨酸蛋白激酶相互作用，并将肌动蛋白细胞骨架连接到质膜上，由此FRMD7蛋白的活性可被减弱或消失。因此，FRMD7突变可能通过破坏控制眼球运动的大脑区域的神经元活动而导致眼球震颤[18-19]。而且，大多数导致ICN的突变都位于FERM结构域[16]。
    2006年，Tarpey等[15]招募了26个X连锁的ICN家系，通过基因分析和研究，发现了第1个眼球震颤基因——FRMD7，首次证实了FRMD7突变是引起ICN的主要原因。同时，他们在人类胚胎大脑和正在发育的神经视网膜中发现了FRMD7的限制性表达，表明FRMD7可能是通过激活GTPase RAC1 在神经突发育中发挥作用，同时证实了FRMD7在眼球运动和凝视稳定性的控制中起着重要的作用。该基因的鉴定为眼动通路的功能和发展研究开启了一扇大门，此后针对C N和FRMD7的研究层出不穷。2008年，Li等[20]通过7个X连锁ICN家系发现了5个新的FRMD7突变，这是首次在中国ICN家系中报道FRMD7新的基因突变类型，进一步证实了FRMD7突变的区域广泛性。Thomas等[16]通过对3 1个X连锁的先天性周期性眼球震颤家系和14例散发病例对照研究，结果显示FRMD7基因突变致病占到了1 0个家系，该研究得出周期性交替性眼球震颤主要与FERM域内的错义突变有关，而且可能是影响了神经元的回路而致病。之后，Chen等[21]报道了1个中国ICN家系中FRMD7基因的新突变和第9号外显子中1个7 bp的缺失(c.823-829delACCCTAC)，这预示了该蛋白的截断，从而扩大了FRMD7基因引起ICN的突变谱，进一步证实FRMD7基因突变是不同种族ICN的潜在病因。
    FRMD7突变是家族性X连锁ICN最常见的原因，与ICN相关的突变包括错义、截断、删除、移码以及无义突变等。表1总结了近年来国内外学者针对FRMD7所致X连锁ICN明确突变位点以及氨基酸改变的研究结果，可供参考。

表1 FRMD7突变所致X连锁ICN列表(共63个)
Table 1 X-linked ICN caused by FRMD7 mutations (63 in total)

20221215113500_5393.jpg

续表1

20221215113559_1065.jpg

    从表1可知，自2006年Tar pey等[15]鉴定出X连锁的ICN致病基因FRMD7以来，共发现各类明确能够引起氨基酸改变的致病突变位点63个。表2显示了FRMD7变异以错义(65%)、截断(14.2%)、删除(9.5%)突变为主，包含移码、无义、复制、沉
默突变，体现了突变类型的丰富性。表3可见X连锁的ICN突变位点主要集中在FRMD7的第7、8、9、12号外显子区域，除了第3和第5号其余外显子区均发现明确致病位点，说明了突变区域的广泛性。报道的病例涉及中国、英国、韩国、美国等10余个国家和地区，也显示了X连锁的ICN在全球发病覆盖的广泛性。

表2 FRMD7所致X连锁ICN突变类型及比例
Table 2 Types and proportions of X-linked ICN mutations caused by FRMD7

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表3 FRMD7所致X连锁ICN外显子突变数目及比例
Table 3 Number and proportion of X-linked ICN exon mutations caused by FRMD7

20221215113943_1100.jpg

2 FRMD7 突变可能的致病机制

    关于ICN，目前学者们在FRMD7基因上鉴定出明确能够引起氨基酸改变的致病突变主要集中在2个关键区域：FERM和FA区域。然而，人们对该蛋白的功能仍然知之甚少。先前的研究[45]表明：FRMD7可通过Rho GTPase信号通路调控神经元的生长和发育，在神经元分化过程中FRMD7的下调会导致神经突发育的改变。在FRMD7中，不同的突变在携带基因的女性中引起不同的外显率，为30%~100%[16,46]。一些家系看起来类似于X连锁显性遗传和一些类似于X连锁隐性遗传，这可能是X连锁显性和隐性ICN基因位点重叠的原因。FRMD7所致不同的ICN患者之间的表型差异(眼球震颤的频率、方向、幅度、是否伴有头位等)可能是不同的突变类型、位点参与和环境共同影响的结果。FRMD7的错义突变和截断突变被预测会通过磷酸化过程受阻、提前终止翻译等方式致使蛋白水平上的严重缺陷和缺失，最终失去功能[32]。另外的删除、移码、无义等突变预计会导致FRMD7蛋白的严重缺陷[22]。
    通过对ICN的小鼠模型研究，Yonehara等[17]发现FRMD7在促进神经元回路方向选择性的不对称性方面起着重要作用。与人类一样，小鼠的水平视动反射也需要FRMD7，它是建立神经元回路不对称的关键调节因子。FRMD7编码的蛋白具有N '端FERM结构域，可能促进信号转导，类似于该家族中具有相同结构域的其他蛋白。他们推测X连锁的ICN可能是因为FRMD7的突变使得涉及视动系统的原发性视网膜在细胞水平上发生了电化学传输缺陷。
    FRMD7突变是X连锁ICN的主要原因，未发现视觉系统缺陷的患者通常表现为X连锁或常染色体显性遗传的先天性眼球震颤[47]。Brodsky等[48]提出CN的病因可能是由于婴幼儿早期大脑发育过程中视觉皮层和皮层下视动通路处于失联状态，来自皮层下视动系统的拮抗运动刺激并促进了不稳定的眼球振荡活动的发展，最终形成眼球震颤。但是基因突变和遗传在这其中扮演了什么样的角色，仍有待于进一步的研究。

3 FRMD7 突变所致其他眼部异常

    有学者[49]通过超高分辨率光学相干断层扫描FRMD7突变所致ICN患者眼底，发现其视盘面积、视网膜神经纤维层厚度、视杯面积、视杯深度均较正常人明显减少，提示视觉传入系统异常发育与FRMD7突变相关，可能是眼球震颤发生的重要病因。然而，与白化病、PAX6突变和色盲等遗传性发育性视网膜疾病相比，ICN患者中央凹发育不全并不显著。视杯、视盘的变化较轻微可能是亚临床的，导致与其他视网膜缺陷相比，FRMD7突变患者的视力更好[22]。此研究结果有待于进一步更多研究样本和数据的支持。
    眼球震颤患者由于不自觉的眼球颤动、视力较差、多存在歪头现象，承受着巨大的生理和社会心理压力。治疗的主要目标是在不影响眼球运动及保持正常注视的前提下，通过减轻异常的眼球震颤来提高患者的视觉质量[50]。目前ICN的治疗手段主要包括光学矫正、手术、药物、中医药等辅助疗法，但是治疗效果尚不理想，只能提高患者的部分视力、减轻有限的眼球震颤和矫正头位。目前关于ICN的发病机制尚无统一共识，治疗手段非常有限，尚不能从根本上解决问题。但新致病基因的发现及其细胞功能的研究、基因亚型的鉴定及动物模型的建立都极大地促进了我们对ICN的认识。这些最新的研究进展为我们今后更清楚地了解直至从病因上治疗ICN提供了源源不断的可靠依据。

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1、云南省“高层次人才培养支持计划”名医专项 (YNWR-MY-2018-006，YNWR-MY-2020-088)；云南省眼部疾病临床医学研究中心开放课题 (YXZX-17)。This work was supported by “High-level Talent Training Support Program” Special Famous Doctors of Yunnan Province (YNWR-MY-2018-006, YNWR-MY-2020-088), and Yunnan Province Eye Disease Clinical Medical Center Internal Project (YXZX-17), China()
2、云南省基础研究计划 ( 昆医联合专项 )[2019FE001(-095)，2019FE001(-169)]；云南省领军人才 (L-2018018)。This work was supported by the Association Foundation Program of Yunnan Provincial Science and Technology Department and Kunming Medical University [2019FE001(-095), 2019FE001(-169)], Leading the Charge of Yunnan Provincial Health System (L-2018018), China()
3、云南省基础研究计划 ( 昆医联合专项 )[2019FE001(-095)，2019FE001(-169)]；云南省领军人才 (L-2018018)；云南省“高层次人才培养支持计划”名医专项 (YNWR-MY-2018-006，YNWR-MY-2020-088)；云南省眼部疾病临床医学研究中心开放课题 (YXZX-17)。This work was supported by the Association Foundation Program of Yunnan Provincial Science and Technology Department and Kunming Medical University [2019FE001(-095), 2019FE001(-169)], Leading the Charge of Yunnan Provincial Health System (L-2018018), ()
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