The Sichuan Provincial Key Laboratory for Human Disease Gene Study, Center for The Sichuan Provincial Key Laboratory for Human Disease Gene Study, Center for Medical Genetics, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, China; Center for Natural Products Research, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu, China; Henan Branch of National Clinical Research Center for Ocular Diseases, Henan Eye Hospital, People's Hospital of Zhengzhou University, Henan Provincial People's Hospital, Zhengzhou, China
Shujin Li
The Sichuan Provincial Key Laboratory for Human Disease Gene Study, Center for The Sichuan Provincial Key Laboratory for Human Disease Gene Study, Center for Medical Genetics, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, China; Center for Natural Products Research, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu, China
The Sichuan Provincial Key Laboratory for Human Disease Gene Study, Center for The Sichuan Provincial Key Laboratory for Human Disease Gene Study, Center for Medical Genetics, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, China; Center for Natural Products Research, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu, China
The Sichuan Provincial Key Laboratory for Human Disease Gene Study, Center for The Sichuan Provincial Key Laboratory for Human Disease Gene Study, Center for Medical Genetics, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, China
Lu Liu
The Sichuan Provincial Key Laboratory for Human Disease Gene Study, Center for The Sichuan Provincial Key Laboratory for Human Disease Gene Study, Center for Medical Genetics, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, China
Ping Fei
Department of Ophthalmology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
Qianchun Xiang
The Sichuan Provincial Key Laboratory for Human Disease Gene Study, Center for The Sichuan Provincial Key Laboratory for Human Disease Gene Study, Center for Medical Genetics, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, China
The Sichuan Provincial Key Laboratory for Human Disease Gene Study, Center for The Sichuan Provincial Key Laboratory for Human Disease Gene Study, Center for Medical Genetics, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, China
Peiquan Zhao
Department of Ophthalmology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
Zhenglin Yang
The Sichuan Provincial Key Laboratory for Human Disease Gene Study, Center for The Sichuan Provincial Key Laboratory for Human Disease Gene Study, Center for Medical Genetics, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, China; Center for Natural Products Research, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu, China; Jinfeng Laboratory, Chongqing, China; Research Unit for Blindness Prevention of Chinese Academy of Medical Sciences (2019RU026), Sichuan Academy of Medical Sciences and Sichuan Provincial People’s Hospital, Chengdu, China
The Sichuan Provincial Key Laboratory for Human Disease Gene Study, Center for The Sichuan Provincial Key Laboratory for Human Disease Gene Study, Center for Medical Genetics, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, China; Center for Natural Products Research, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu, China; Henan Branch of National Clinical Research Center for Ocular Diseases, Henan Eye Hospital, People's Hospital of Zhengzhou University, Henan Provincial People's Hospital, Zhengzhou, China; Jinfeng Laboratory, Chongqing, China; Research Unit for Blindness Prevention of Chinese Academy of Medical Sciences (2019RU026), Sichuan Academy of Medical Sciences and Sichuan Provincial People’s Hospital, Chengdu, China
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 in calcyphosine-like gene (CAPSL) that is associated with FEVR. Both variants exhibited compromised CAPSL protein expression. Vascular endothelial cell (EC)-specific inactivation of Capsl resulted in delayed radial/vertical vascular progression, compromised endothelial proliferation/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. Transcriptomic and proteomic profiling 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 uncovered similar transcription patterns. Collectively, this study reports a novel FEVR-associated candidate gene, CAPSL, which provides valuable information for genetic counseling of FEVR. This study also reveals that compromised CAPSL function may cause FEVR through MYC axis, shedding light on the potential involvement of MYC signaling in the pathogenesis of FEVR.
