Familial exudative vitreoretinopathy (FEVR) is a severe genetic disorder characterized by incomplete vascularization of the peripheral retina and associated symptoms that can lead to vision loss. However, the underlying genetic causes of approximately 50% of FEVR cases remain unknown. Here, we report two heterozygous variants, c.88C＞T (p.Arg30Ter) and c.247C＞T (p.Leu83Phe), in calcyphosine like (CAPSL), from four patients in two unrelated FEVR-affected families. Both variants exhibited compromised CAPSL protein expression. Vascular endothelial cell-specific inactivation of Capsl in postnatal mice resulted in defective sprouting, delayed radial/vertical vascular progression, compromised endothelial proliferation, and impaired cell migration, recapitulating the human FEVR phenotypes. CAPSL-depleted human retinal microvascular endothelial cells (HRECs) exhibited impaired tube formation, decreased cell proliferation, disrupted cell polarity establishment and filopodia/lamellipodia formation, as well as disrupted collective cell migration in vitro. Transcriptomic and proteomic profiling of CAPSL-depleted HRECs revealed that CAPSL abolition inhibited the MYC signaling axis, in which the expression of core MYC targeted genes were profoundly decreased. Furthermore, a combined analysis of CAPSL-depleted HRECs and c-MYC-depleted human umbilical vein endothelial cells (HUVECs) uncovered similar transcription patterns. Collectively, this study reports a novel FEVR-associated candidate gene, CAPSL, which provides invaluable information for genetic counseling and prenatal diagnosis of FEVR. This study also reveals that compromised CAPSL function causes FEVR through MYC axis, shedding light on the potential involvement of MYC signaling in the pathogenesis of FEVR.

The authors have declared no competing interest.

This study was supported by the National Natural Science Foundation of China (82371083, 82121003, 82101153, 82101160), the Department of Science and Technology of Sichuan Province (2023ZYD0172, 2023NSFSC1661, 2023NSFSC0036, and 2022ZYD0059), the CAMS Innovation Fund for Medical Sciences (2019-12M-5-032), Sichuan Intellectual Property Office (China) (No. 2022-ZS-0070), the Fundamental Research Funds for the Central Universities of Ministry of Education of China (ZYGX2022J023), and Sichuan Provincial People Hospital Postdoctoral fund (2022BH019). The funders had no role in the study design, data collection and analysis, or preparation of the manuscript.

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This study was approved by the institutional review board (IRB) of Sichuan Provincial People Hospital (approval number: 2014-009).

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