An SNX31 variant underlies dominant familial exudative vitreoretinopathy-like pathogenesis.

Familial exudative vitreoretinopathy (FEVR) is a complex hereditary eye disorder characterized by incomplete development of the retinal vasculature, thereby affecting retinal angiogenesis. But the genetic factors contributing to its development or pathogenesis remain elusive. In a Chinese FEVR family with 19 members, by utilizing whole exome sequencing, we identified a candidate disease-causing DNA variant in sorting nexin 31 (SNX31) (c.963delG; p. Trp321Cys), which results in a frameshift mutation. Herein we studied the biochemical mechanism of this mutation and uncovered that it is deficient in β1-integrin binding and integrin stability. The SNX31 c.963delG point mutation mouse model (SNX31m/m) was constructed using CRISPR/Cas9 technology. At 2-4 months of age, SNX31m/m mice showed fundus phenotypes similar to FEVR-like changes, including vascular leakage and retinal atrophy. Moreover, we found that VEGF and apoptotic pathways were involved in these ocular phenotypes. At present, the FEVR-like mouse model is mainly constructed by intravitreal injection, and we are the first to construct it by gene knockout. Hence our study extended FEVR mutation spectrum to include SNX31. Meanwhile, these findings expanded our understanding of the molecular pathogenesis of FEVR and may facilitate the development of methods for the diagnosis and prevention of FEVR patients.