Sichuan Provincial Key Laboratory for Human Disease Gene Study, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan, China.
Research Unit for Blindness Prevention of Chinese Academy of Medical Sciences (2019RU026), Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, Chengdu, Sichuan, China.
Clin Exp Ophthalmol. 2022 May;50(4):441-448. doi: 10.1111/ceo.14037. Epub 2022 Feb 7.
BACKGROUND: Familial exudative vitreoretinopathy (FEVR) is an inherited ocular disease with clinical manifestations of aberrant retinal vasculature. We aimed to identify novel causative variants responsible for FEVR and provided evidence for the genetic counselling of FEVR. METHODS: We applied whole-exome sequencing (WES) on the genomic DNA samples from the probands and performed Sanger sequencing for variant validation. Western blot analysis and luciferase assays were performed to test the expression levels and the activity of mutant proteins. RESULTS: We identified one novel heterozygous nonsense variant, and three novel heterozygous frameshift variants including c.1801G>T (p.G601*), c.1965delC (p.H656Tfs41), c.4445delC (p.S1482Cfs17), and c.4482delC (p.P1495Rfs*4), which disabled the function of LRP5 on the Norrin/β-catenin signalling. Overexpression of variant-carrying LRP5 proteins resulted in down regulation of the protein levels of β-catenin and the Norrin/β-catenin signalling target genes c-Myc and Glut1. CONCLUSION: Our study showed that four inherited LRP5 variants can cause autosomal dominant FEVR via down regulation of Norrin/β-catenin signalling and expanded the spectrum of FEVR-associated LRP5 variants.
背景：家族渗出性玻璃体视网膜病变（FEVR）是一种具有异常视网膜血管表型的遗传性眼病。我们旨在鉴定导致 FEVR 的新的致病变异，并为 FEVR 的遗传咨询提供证据。
方法：我们对先证者的基因组 DNA 样本进行了全外显子组测序（WES），并进行了 Sanger 测序以验证变异。进行 Western blot 分析和荧光素酶测定来检测突变蛋白的表达水平和活性。
结果：我们发现了一个新的杂合性无义变异，以及三个新的杂合性移码变异，包括 c.1801G>T（p.G601*）、c.1965delC（p.H656Tfs41）、c.4445delC（p.S1482Cfs17）和 c.4482delC（p.P1495Rfs*4），这些变异使 LRP5 失去了对 Norrin/β-catenin 信号的功能。携带变异的 LRP5 蛋白的过表达导致 β-catenin 蛋白水平和 Norrin/β-catenin 信号靶基因 c-Myc 和 Glut1 的下调。
结论：我们的研究表明，四个遗传性 LRP5 变异可通过下调 Norrin/β-catenin 信号导致常染色体显性 FEVR，并扩展了与 FEVR 相关的 LRP5 变异谱。
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