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Lin Zhang, Shanshan Zhang, Xianjun Zhu, Zhenglin Yang; Mutations in JAG1 Gene May Lead to Familial Exudative Vitreoretinopathy. Invest. Ophthalmol. Vis. Sci. 2018;59(9):1434.
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© ARVO (1962-2015); The Authors (2016-present)
Familial exudative vitreoretinopathy (FEVR) is a severe inherited retina disease. To data, mutations in at least 6 genes can lead to FEVR: NDP, FZD4, LRP5, TSPAN12, CTNNB1 and ZNF408. However, mutations in these genes can only account for 50% of FEVR case. To identify new mutations or genes that can cause FEVR.
Whole-exome sequencing (WES) method was used to screen the possible mutations that cause FEVR, and Sanger sequencing was used to verify the mutations. Then, we generated conditional knockout mice using Pdgfb-Cre-loxp system to study if loss of Jag1 gene can lead to FEVR phenotypes.
We identified 3 possibly causative JAG1 mutations in 3 Han Chinese FEVR patients: c.413C>T (p. A138V), c.1415G>A (p. R472H) and c. 2884A>G (p. T962A). Luciferase assays demonstrated the mutant JAG1 proteins all partially lost their activities. Further animal model experiments shown that when JAG1 expression was removed from retinal endothelial cells, the development of retinal vascular were impaired, and partially copied the FEVR phenotypes. Mechanically, we revealed that the expression of JAG1 is regulated by Norrin-β-catenin-Sox17 signaling pathway.
Taken together, we demonstrated that mutations in JAG1 gene may lead to FEVR.
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.
Identification of mutations in JAG1 gene in 3 FEVR patients.
Impaired retinal vascular development in Jag1-CKO mice.
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