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ENGLISH ABSTRACT
RS1基因突变的X连锁视网膜劈裂症家系基因型和表型分析
蔡博
刘洋
朴顺玉
王少林
李文静
陈琳
田恬
薛雅珺
庄文娟
作者及单位信息
·
DOI： 10.3760/cma.j.cn115985-20190711-00307
A phenotype-genotype study of X-linked retinoschisis in RS1 mutations
Cai Bo
Liu Yang
Piao Shunyu
Wang Shaolin
Li Wenjing
Chen Lin
Tian Tian
Xue Yajun
Zhuang Wenjuan
Authors Info & Affiliations
Cai Bo
Clinical Medicine College, Ningxia Medical University, Yinchuan 750001, China
Liu Yang
Department of Ophthalmology, Ning Xia Eye Hospital, People's Hospital of Ningxia Hui Autonomous Region, First Affiliated Hospital of Northwest University for Nationalities, Ningxia Clinical Research Center on Diseases of Blindness in Eye, Yinchuan 750001, China
Piao Shunyu
Department of Ophthalmology, Ning Xia Eye Hospital, People's Hospital of Ningxia Hui Autonomous Region, First Affiliated Hospital of Northwest University for Nationalities, Ningxia Clinical Research Center on Diseases of Blindness in Eye, Yinchuan 750001, China
Wang Shaolin
Department of Ophthalmology, Ning Xia Eye Hospital, People's Hospital of Ningxia Hui Autonomous Region, First Affiliated Hospital of Northwest University for Nationalities, Ningxia Clinical Research Center on Diseases of Blindness in Eye, Yinchuan 750001, China
Li Wenjing
Clinical Medicine College, Ningxia Medical University, Yinchuan 750001, China
Chen Lin
Clinical Medicine College, Ningxia Medical University, Yinchuan 750001, China
Tian Tian
Clinical Medicine College, Ningxia Medical University, Yinchuan 750001, China
Xue Yajun
Department of Ophthalmology, Ning Xia Eye Hospital, People's Hospital of Ningxia Hui Autonomous Region, First Affiliated Hospital of Northwest University for Nationalities, Ningxia Clinical Research Center on Diseases of Blindness in Eye, Yinchuan 750001, China
Zhuang Wenjuan
Department of Ophthalmology, Ning Xia Eye Hospital, People's Hospital of Ningxia Hui Autonomous Region, First Affiliated Hospital of Northwest University for Nationalities, Ningxia Clinical Research Center on Diseases of Blindness in Eye, Yinchuan 750001, China
·
DOI： 10.3760/cma.j.cn115985-20190711-00307
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摘要

目的检测3个X连锁视网膜劈裂症(XLRS)家系的致病基因，探讨其基因型和表型特征。

方法采用横断面研究方法，纳入2017年10月至2019年3月在宁夏眼科医院就诊的3个先天性视网膜劈裂家系，收集患者和家系成员的临床资料，采集受检者外周血，完善眼科检查并进行临床分期，通过Panel测序筛选致病基因，利用软件工具对突变进行保守性分析、致病性分析和蛋白质结构预测，并根据ACGM指南分析突变的致病性。

结果3个家系共5例青年患者，黄斑光相干断层扫描(OCT)均出现典型的黄斑区视网膜劈裂腔，表现为视网膜劈裂症Ⅰ期；1例中年患者表现为视网膜劈裂症Ⅲ期的黄斑萎缩改变；Panel测序分别发现 RS1基因突变c.668G>A、c.618G>A和外显子1缺失，其中C223和W206在哺乳动物中高度保守，软件预测突变具有致病性且蛋白质结构改变；外显子1缺失突变没有进行保守性分析和蛋白结构的预测。根据ACGM指南分析3个突变均为致病性变异。

结论 RS1基因突变c.668G>A/p.C223Y、c.618G>A/p.W206X和外显子1缺失均为中国XLRS家系的致病性突变。Panel测序联合致病性预测软件工具的应用对遗传性视网膜疾病的诊断及致病基因的确定有重要作用。

X连锁视网膜劈裂症; RS1基因 ;突变
ABSTRACT

ObjectiveTo describe the characteristics of genotype and phenotype in 3 families with X-linked retinoschisis (XLRS) due to RS1 mutations.

MethodsA cross-sectional approach was adopted.Three XLRS families at the Ningxia Eye Hospital from October 2017 to March 2019 were included.Clinical data and peripheral blood of patients and related families were collected and clinically staged were formulated through a comprehensive eye examination.The disease-causing genes screened by panel sequencing underwent conservative analysis, pathogenicity analysis and protein structure prediction by software tools.Analysis of the mutations pathogenicity was performed according to the American College of Medical Genetics and Genomics guidelines.The research was approved by Medical Ethics Committee of the People's Hospital of Ningxia Hui Autonomous Region and followed the Declaration of Helsinki.Written informed consent was obtained from each participant.

ResultsTotal 5 young male patients and 1 middle-aged patient in these three families.The optical coherence tomography(OCT) findings of 5 young patients showed typical macular retinoschisis, which were characterized by stage I of XLRS.One middle-aged patient (Ⅱ-9) showed a stage Ⅲ lesion of macular atrophy.The mutations of c. 668G>A, c.618G>A and exon 1 deletion in RS1 gene were found in the three families.C223 and W206 were verified to be highly conserved in mammals and were predicted to be pathogenic mutations by software and the change of protein structure.Conservation analysis and prediction of protein structure were not performed for the mutation of exon 1 deletion.All the mutations were pathogenic variants according to the ACGM guidelines.

ConclusionsMutations of c. 668G>A/p.C223Y, c.618G>A/p.W206X and exon 1 deletion in RS1 gene are pathogenic mutations in Chinese XLRS families.The combination of Panel sequencing with pathogenicity analysis and protein structure prediction have important effect to diagnosis and identify the causative genes for the hereditary retinal diseases.

X-linked retinoschisis; RS1 gene ;Mutation
Zhuang Wenjuan, Email: mocdef.3ab61jnew_hz
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引用本文

蔡博,刘洋,朴顺玉,等. RS1基因突变的X连锁视网膜劈裂症家系基因型和表型分析 [J]. 中华实验眼科杂志,2020,38(04)：322-330.

DOI:10.3760/cma.j.cn115985-20190711-00307

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先天性视网膜劈裂是罕见的视网膜玻璃体变性疾病，以X连锁视网膜劈裂症(X-linked rentinoschisis，XLRS)多见 [ 1 , 2 ]。XLRS是一种与X染色体上 RS1基因有关的隐性遗传的视网膜劈裂，患病率为1/25 000～1/5 000，是男性青少年黄斑变性的常见原因之一，女性携带者常为正常表型 [ 3 , 4 ]。XLRS由Hass首次报道 [ 5 ]，Sauer等 [ 6 ]1997年由Sauge [ 6 ]确定其致病原因是 RS1基因突变。XLRS的特征性临床表现是双侧黄斑区车辐状图案样病变，黄斑区有视网膜层间劈裂囊腔，可发生于不同的视网膜层，其中多为内核层劈裂，神经纤维层、内丛状层、外丛状层和外核层较少见。约50%的患者伴周边视网膜劈裂，极少数患者劈裂仅发生于周边视网膜 [ 8 ]。与其他视网膜病变一样，XLRS患者的全视野视网膜电图(electroretinogram，ERG)也可出现负性波形 [ 9 , 10 ]。XLRS患儿多于学龄期因视力下降就诊，同时可伴有眼球震颤、斜视、白内障、玻璃体积血或者视网膜脱离等 [ 11 , 12 ]。光相干断层扫描(optical coherence tomography，OCT)在XLRS的诊断中具有突出的优势。 RS1基因(NM-000330)是XLRS已知的常见致病基因，位于X染色体短臂22区，共6个外显子，编码一个由224个氨基酸组成的蛋白质Rentinoschisin(RS)，为一种八聚复合体功能蛋白 [ 12 , 13 ]。RS主要表达于视网膜的光感受器和双极细胞，在维持光感受器和双极细胞的结构和功能中有重要作用 [ 11 , 14 ]。本研究中通过对3个XLRS家系进行临床评估、Panel测序以及生物信息学致病性分析，探寻其遗传学及临床表型的特征，预测疾病的转归。
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庄文娟，Email： mocdef.3ab61jnew_hz
B
所有作者均声明不存在任何利益冲突
C
国家自然科学基金项目 (81460093)
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