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An SNX31 variant underlies dominant familial exudative vitreoretinopathy-like pathogenesis
Ningda Xu, … , Jing Li, Lvzhen Huang
Ningda Xu, … , Jing Li, Lvzhen Huang
Published April 13, 2023
Citation Information: JCI Insight. 2023;8(10):e167032. https://doi.org/10.1172/jci.insight.167032.
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Research Article Genetics Ophthalmology Article has an altmetric score of 2

An SNX31 variant underlies dominant familial exudative vitreoretinopathy-like pathogenesis

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Abstract

Familial exudative vitreoretinopathy (FEVR) is a complex hereditary eye disorder characterized by incomplete development of the retinal vasculature, which thereby affects retinal angiogenesis. But the genetic factors contributing to FEVR’s development or pathogenesis remain elusive. In a Chinese family with FEVR with 19 members, by using 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. We studied the biochemical mechanism of this mutation and determined that it is deficient in β1-integrin binding and stability. The SNX31 c.963delG point mutation mouse model (SNX31m/m) was constructed with 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. Hence, our study extended the FEVR mutation spectrum to include SNX31. 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.

Authors

Ningda Xu, Yi Cai, Jiarui Li, Tianchang Tao, Caifei Liu, Yan Shen, Xiaoxin Li, Leiliang Zhang, Mingwei Zhao, Xuan Shi, Jing Li, Lvzhen Huang

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Figure 5

Immunofluorescence staining of SNX31, β1-integrin, and CD31 in retinas of WT and SNX31m/m mice.

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Immunofluorescence staining of SNX31, β1-integrin, and CD31 in retinas o...
(A) SNX31 expression in retinal sections of 2-month-old WT and SNX31m/m mice. SNX31 fluorescence signal localized around blood vessels. White arrows show the fluorescent signal of SNX31; black arrows indicate RPE disruption and thinning of the outer nuclear layer above. Red, SNX31; blue, Hoechst-stained nuclei. (B) β1-integrin expression in retinal sections of 2-month-old WT and SNX31m/m mice. Red, β1-integrin; blue, Hoechst-stained nuclei. (C) CD31 expression in retinal sections of 2-month-old WT and SNX31m/m mice. Red, CD31; blue, Hoechst-stained nuclei. (D and E) Comparison of retinal β1-integrin mRNA and protein expression in WT and SNX31m/m mice at 1, 2, and 4 months of age. Statistical analysis was performed via unpaired parametric t test. Data are shown as mean ± SEM. *P < 0.05. See complete unedited blots in the supplemental material.

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