Exome sequencing revealed Notch ligand JAG1 as a novel candidate gene for familial exudative vitreoretinopathy
L Zhang, X Zhang, H Xu, L Huang, S Zhang, W Liu… - Genetics in …, 2020 - nature.com
Genetics in Medicine, 2020•nature.com
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 …
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 …
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.
nature.com