Affiliation:
1. 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
2. Center for Natural Products Research, Chengdu Institute of Biology, Chinese Academy of Sciences;
3. Research Unit for Blindness Prevention of Chinese Academy of Medical Sciences (2019RU026), Sichuan Academy of Medical Sciences and Sichuan Provincial People’s Hospital
4. Department of Ophthalmology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine
Abstract
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.
Publisher
eLife Sciences Publications, Ltd