Whole Exome Sequencing Analysis Identifies Mutations in LRP5 in Indian Families with Familial Exudative Vitreoretinopathy
Whole Exome Sequencing Analysis Identifies Mutations in LRP5 in Indian Families with Familial Exudative Vitreoretinopathy
复制标题
全外显子组测序分析确定印度家族性渗出性玻璃体视网膜病变家族中 LRP5 突变
DOI：
10.1089/gtmb.2015.0322
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发表时间：
2016
影响因子：
1.4
通讯作者：
Zhu Xianjun
中科院分区：
文献类型：
--
作者：
Zhang Lin;Yang Yeming;Li Shujin;Tai Zhengfu;Huang Lulin;Liu Yuqing;Zhu Xiong;Di Yanan;Qu Chao;Jiang Zhilin;Li Yuanfeng;Zhang Guolin;Kim Ramasamy;Sundaresan Periasamy;Yang Zhenglin;Zhu Xianjun
背景家族性渗出性玻璃体视网膜病变(FEVR，OMIM 133780)是一种以视网膜血管发育不全和新生血管为特征的严重遗传性视网膜疾病。据报道，至少有5个基因与FEVR有关，包括NDP、LRP5、FZD4、TSPAN12和ZNF408。最近报道的数据显示，KIF11基因的突变也会导致FEVR。目的调查4个FEVR印度家系的致病基因突变。方法对4个FEVR先证者的基因组DNA样本进行Whole外显子测序，并用Sanger测序法对所有已发现的基因多态性进行验证。结果在这些FEVR家系中发现了4个新的LRP5错义突变：c.C1042T(p.R348W)、c.G1141A(p.D381N)、c.C1870T(p.R624W)和c.A4550G(p.Y1517C)。荧光素酶检测结果显示，这4个LRP5突变均导致去甲肾上腺素引起的酶活性显著降低，提示它们是致病的。结论我们的发现扩大了印度人群FEVR的突变谱，为临床诊断提供了一定的指导意义。
BackgroundFamilial exudative vitreoretinopathy (FEVR, OMIM 133780) is a severe inherited retinal disorder characterized by incomplete retinal vascular development and neovascularization. At least five genes have been reported to be associated with FEVR, includingNDP,LRP5,FZD4,TSPAN12, andZNF408. Recently reported data showed that mutations in theKIF11gene can also lead to FEVR conditions. Previous studies suggested that known mutations only explain approximately 40–60% of FEVR cases in different populations.PurposeTo investigate the causative genetic mutations in four Indian families with FEVR.MethodsWhole exome sequencing was carried out to analyze the genomic DNA samples from the four FEVR proband patients and Sanger sequencing was utilized to verify all identified polymorphisms. A luciferase assay was used to test the mutant protein activity.ResultsWe identified four novelLRP5missense mutations in these FEVR families: c.C1042T (p.R348W), c.G1141A (p.D381N), c.C1870T (p.R624W), and c.A4550G (p.Y1517C). The luciferase assay demonstrated that all four of these LRP5 mutations led to significant reduction of enzymatic activity with response to NORRIN, suggesting that they are pathogenic.ConclusionOur findings expand the mutational spectrum of FEVR in the Indian population and provide some guidelines in clinical diagnosis.