Exome sequencing revealed Notch ligand JAG1 as a novel candidate gene for familial exudative vitreoretinopathy

被引:48
|
作者
Zhang, Lin [1 ]
Zhang, Xiang [2 ]
Xu, Huijuan [3 ]
Huang, Lulin [1 ]
Zhang, Shanshan [1 ]
Liu, Wenjing [1 ]
Yang, Yeming [1 ]
Fei, Ping [2 ]
Li, Shujin [1 ]
Yang, Mu [3 ]
Zhao, Peiquan [2 ]
Zhu, Xianjun [1 ,3 ,4 ]
Yang, Zhenglin [1 ,3 ]
机构
[1] Univ Elect Sci & Technol China, Sch Med, Sichuan Prov Peoples Hosp, Sichuan Prov Key Lab Human Dis Gene Study, Chengdu, Sichuan, Peoples R China
[2] Shanghai Jiao Tong Univ, Dept Ophthalmol, Sch Med, Xinhua Hosp, Shanghai, Peoples R China
[3] Chinese Acad Sci, Chengdu Inst Biol, Chengdu, Peoples R China
[4] Sichuan Acad Med Sci & Sichuan Prov Peoples Hosp, Inst Lab Anim Sci, Chengdu, Sichuan, Peoples R China
基金
中国国家自然科学基金;
关键词
familial exudative vitreoretinopathy; exome sequencing; JAG1; angiogenesis; knockout mouse model; RETINAL ANGIOGENESIS; MUTATIONS; JAGGED1; FRIZZLED-4; ACTIVATION; DEFECTS; DISEASE; LOCUS; LRP5; DLL4;
D O I
10.1038/s41436-019-0571-5
中图分类号
Q3 [遗传学];
学科分类号
071007 ; 090102 ;
摘要
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.
引用
收藏
页码:77 / 84
页数:8
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