外显子组测序揭示 Notch 配体 JAG1 是家族性渗出性玻璃体视网膜病变的一个新候选基因。
Exome sequencing revealed Notch ligand JAG1 as a novel candidate gene for familial exudative vitreoretinopathy.
机构信息
Sichuan Provincial Key Laboratory for Human Disease Gene Study, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, China.
Department of Ophthalmology, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China.
出版信息
Genet Med. 2020 Jan;22(1):77-84. doi: 10.1038/s41436-019-0571-5. Epub 2019 Jul 5.
PURPOSE
Familial exudative vitreoretinopathy (FEVR) is a blindness-causing retinal vascular disease characterized by incomplete vascularization of the peripheral retina and by the absence or abnormality of the second/tertiary capillary layers in the deep retina. Variants in known FEVR disease genes can only explain about 50% of FEVR-affected cases. We aim to identify additional disease genes in patients with FEVR.
METHODS
We applied exome sequencing analysis in a cohort of 49 FEVR families without pathogenic variants in known FEVR genes. Functions of the affected proteins were evaluated by reporter assay. Knockout mouse models were generated by endothelial-specific Cre line.
RESULTS
Three novel rare heterozygous variants in Notch ligand JAG1 were identified in FEVR families-c.413C>T p. (A138V), c.1415G>A p. (R472H), and c.2884A>G p. (T962A)-and verified by Sanger sequencing analysis. Notch reporter assay revealed that mutant JAG1 proteins JAG1-A138V and JAG1-T962A lost almost all of their activities, and JAG1-R472H lost approximately 50% of its activity. Deletion of Jag1 in mouse endothelial cells resulted in reduced tip cells at the angiogenic front and retarded vessel growth, reproducing FEVR-like phenotypes.
CONCLUSION
Our data suggest that JAG1 is a novel candidate gene for FEVR and pinpoints a potential target for therapeutic intervention.
目的
家族渗出性玻璃体视网膜病变（FEVR）是一种致盲性视网膜血管疾病，其特征为周边视网膜血管化不完全，以及深层视网膜的第二/三级毛细血管层缺失或异常。已知 FEVR 疾病基因的变异只能解释约 50%的 FEVR 受影响病例。我们旨在鉴定 FEVR 患者中的其他疾病基因。
方法
我们对 49 个无已知 FEVR 基因致病性变异的 FEVR 家系进行外显子组测序分析。通过报告基因检测评估受影响蛋白的功能。通过内皮细胞特异性 Cre 线生成基因敲除小鼠模型。
结果
在 FEVR 家系中鉴定出三种新的罕见杂合变异 Notch 配体 JAG1 c.413C>T p. (A138V)、c.1415G>A p. (R472H) 和 c.2884A>G p. (T962A)，并通过 Sanger 测序分析验证。Notch 报告基因检测显示突变 JAG1 蛋白 JAG1-A138V 和 JAG1-T962A 几乎丧失了所有活性，而 JAG1-R472H 丧失了约 50%的活性。在小鼠内皮细胞中敲除 Jag1 导致血管生成前沿的尖端细胞减少和血管生长迟缓，重现 FEVR 样表型。
结论
我们的数据表明 JAG1 是 FEVR 的一个新候选基因，并指出了一个潜在的治疗干预靶点。
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