Lin Zhang1, Xiang Zhang2, Huijuan Xu3, Lulin Huang1, Shanshan Zhang1, Wenjing Liu1, Yeming Yang1, Ping Fei2, Shujin Li1, Mu Yang3, Peiquan Zhao4, Xianjun Zhu5,6,7, Zhenglin Yang8,9. 1. 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. 2. Department of Ophthalmology, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China. 3. Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu, China. 4. Department of Ophthalmology, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China. zhaopeiquan@xinhuamed.com.cn. 5. 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. xjzhu@uestc.edu.cn. 6. Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu, China. xjzhu@uestc.edu.cn. 7. Institute of Laboratory Animal Sciences, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, Chengdu, Sichuan, China. xjzhu@uestc.edu.cn. 8. 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. zhenglin.yang@hsc.utah.edu. 9. Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu, China. zhenglin.yang@hsc.utah.edu.
Abstract
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.
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.
Authors: James Wawrzynski; Aara Patel; Abdul Badran; Isaac Dowell; Robert Henderson; Jane C Sowden Journal: Front Genet Date: 2022-05-16 Impact factor: 4.772