中华眼底病杂志

中华眼底病杂志

家族性渗出性玻璃体视网膜病变患者基因突变检测结果及临床特征分析

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目的观察家族性渗出性玻璃体视网膜病变(FEVR)患者Norrie病(NDP)、卷曲蛋白4(FZD4)、低密度脂蛋白受体相关蛋白5(LRP5)、四旋蛋白12(TSPAN12)基因突变与临床表型。方法回顾性系列病例研究。4个无血缘关系家系的9例FEVR患者的18只眼和5名家系中正常成员纳入研究。详细收集患者病史、家族史;患者以及家系正常成员均行最佳矫正视力、裂隙灯显微镜、眼底彩色照相、荧光素眼底血管造影(FFA)检查。采集患者及其家系正常成员外周静脉血,提取全基因组DNA。采用聚合酶链反应扩增候选致病基因NDP、FZD4、LRP5、TSPAN12的全部外显子编码区及连接非转录的序列,直接测序法检测潜在致病基因突变。Polyphen2和SIFT软件明确该基因突变位点的有害性及可能引起的蛋白结构改变。结果DNA测序结果发现,家系2患者(Ⅰ1、Ⅱ1)第6外显子存在c.1330C>T(p.R444C)错义突变。Polyphen2程序预测分析结果显示,蛋白替换分值为0.882;SIFT分析提示为致病性突变。先证者(Ⅱ1)双眼呈现不同程度的周边血管发育停滞、血管纡曲、纤维血管形成。FFA检查可见左眼视盘、黄斑向颞侧牵拉,颞侧血管走行平直,呈毛刷状,周边可见新生血管及大片无灌注区。其父亲(Ⅰ1)双眼视网膜周边血管异常,走行平直,呈毛刷状。家系中所有受检者FZD4、NDP、TSPAN12基因均未检测到突变位点。结论LRP5基因突变位点c.1330C>T (p.R444C)是FEVR患者的致病基因;相同基因突变位点,具有不同临床表型。

ObjectiveTo identify mutations in NDP, FZD4, LRP5, TSPAN12 in Chinese families with familial exudative vitreoretinopathy (FEVR) and observe the clinical features.MethodsRetrospective case series study. The 9 patients (18 eyes) and 5 normal members from 4 unrelated families were included in the study. The patients medical history and family history were collected in detail. All patients underwent best corrected visual acuity (BCVA), slit-lamp biomicroscopy, fundus colorized photography, fundus fluorescein angiography (FFA). Genomic DNA were collected from all the patients. Mutations were detected by directly sequencing to the whole coding region and exon-intron boundaries of NDP, FZD4, LRP5 and TSPAN12 gene. Polyphen and SIFT programs were used to predict the effects on the structure and functional properties of mutant protein.ResultsThere were two affected individuals in the family 2 carried LRP5 gene mutation [c.1330C>T (p.R444C )] in exon 6 by sequence analysis. A score of 0.882 was acquired by Polyphen program analysis. And the missense change was predicted to be pathogenic by SIFT. Fundus changes of the proband showed angioplasia, tortuosity of peripheral vessels. And temporal dragging of the optic disc, peripheral avascular zone, neovascularization were found in FFA. Brush-like and straight of peripheral vessels were found in Ⅰ1. No variant was found in NDP, FZD4 and TSPAN12 gene.ConclusionOur study supports the gene mutation c.1330C>T (p.R444C) of LRP5 is pathogenesis of FEVR. Patients with the same mutation could have variable phenotypic characteristics.

关键词: 视网膜疾病/遗传学; 视网膜疾病/病因学; 基因; 突变; 序列分析

Key words: Retinal diseases/genetics; Retinal diseases/etiology; Genes; Mutation; Sequence analysis

引用本文: 张桐梅, 韩梅, 应铭, 郝朋, 韩瑞芳. 家族性渗出性玻璃体视网膜病变患者基因突变检测结果及临床特征分析. 中华眼底病杂志, 2018, 34(6): 556-561. doi: 10.3760/cma.j.issn.1005-1015.2018.06.007 复制

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