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Invest Ophthalmol Vis Sci. 2020 Feb 7;61(2):39. doi: 10.1167/iovs.61.2.39.
Familial exudative vitreoretinopathy (FEVR) is an inherited retinal disease in which the retinal vasculature is affected. Patients with FEVR typically lack or have abnormal vasculature in the peripheral retina, the outcome of which can range from mild visual impairment to complete blindness. A missense mutation (p.His455Tyr) in ZNF408 was identified in an autosomal dominant FEVR family. Little, however, is known about the molecular role of ZNF408 and how its defect leads to the clinical features of FEVR.
Using CRISPR/Cas9 technology, two homozygous mutant zebrafish models with truncated znf408 were generated, as well as one heterozygous and one homozygous missense znf408 model in which the human p.His455Tyr mutation is mimicked.
Intriguingly, all three znf408-mutant zebrafish strains demonstrated progressive retinal vascular pathology, initially characterized by a deficient hyaloid vessel development at 5 days postfertilization (dpf) leading to vascular insufficiency in the retina. The generation of stable mutant lines allowed long-term follow up studies, which showed ectopic retinal vascular hyper-sprouting at 90 dpf and extensive vascular leakage at 180 dpf.
Together, our data demonstrate an important role for znf408 in the development and maintenance of the vascular system within the retina.
家族性渗出性玻璃体视网膜病变（FEVR）是一种遗传性视网膜疾病，其视网膜血管受到影响。FEVR 患者的周边视网膜通常缺乏或存在异常的血管，其结果范围从轻度视力障碍到完全失明。在一个常染色体显性遗传的 FEVR 家族中发现了 ZNF408 中的错义突变（p.His455Tyr）。然而，人们对 ZNF408 的分子作用及其缺陷如何导致 FEVR 的临床特征知之甚少。
使用 CRISPR/Cas9 技术，生成了两个截短型 znf408 的纯合突变斑马鱼模型，以及一个模拟人类 p.His455Tyr 突变的杂合和纯合错义 znf408 模型。
有趣的是，所有三种 znf408 突变的斑马鱼品系都表现出进行性的视网膜血管病理学，最初表现为在受精后 5 天（dpf）时缺乏玻璃样血管发育，导致视网膜血管不足。稳定突变系的产生允许进行长期的后续研究，显示在 90 dpf 时有异位视网膜血管过度发芽，在 180 dpf 时有广泛的血管渗漏。
总之，我们的数据表明 znf408 在视网膜血管系统的发育和维持中起着重要作用。
