EPAS1 gain-of-function mutation causes ocular manifestations in HIF-2α paraganglioma-somatostatinoma-polycythemia syndrome

Abstract

Purpose : Hypoxia-inducible transcription factors (HIFs) are critically important in the development of retinal vasculature. A new syndrome of paraganglioma, somatostatinoma and secondary polycythemia (Pacak-Zhuang syndrome) caused by somatic gain-of-function EPAS1 mutations has recently been described. In addition to the systemic manifestations, poor visual acuity and ocular anomalies have been identified in patients with this syndrome. To assess the pathogenic effects of EPAS1 mutation and the resultant pseudo-hypoxic state in vivo, we developed a transgenic murine model with a gain-of-function Epas1 mutation. In this study, we compared the retinal abnormalities in patients with Pacak-Zhuang syndrome to the retinal lesions that we identified in the Epas1 mutation murine model.

Methods : Epas1^A529V mutant mice (corresponding to human EPAS1^A530V) were established by TALEN-mediated homologous recombination. Funduscopic examinations and fundus photography were performed with a custom-made Xenon Nova Storz Endoscope attached to a Nikon D90 camera. Fluorescein angiography of the retina was performed using a Phoenix Micron III retinal imaging system.

Results : Vessel dilation with exudates, macular edema, neovascularization, and fibrosis over the optic disc have been described in patients with EPAS1 mutations. We evaluated the Epas1 mutation murine model and observed optic disc fibrosis, vessel tortuosity and vessel dilation in the mutant mice but not in the littermate control mice by funduscopic imaging. Fluorescein angiography also revealed leakage from vessels surrounding the optic nerve in the mutant mice, suggesting compromised retinal vessel integrity.

Conclusions : Our results implicate the EPAS1 mutation and resultant pseudo-hypoxic state in the development of the observed ocular phenotypes in patients with HIF-2α paraganglioma-somatostatinoma-polycythemia syndrome. Thus, further investigation into the mechanism of EPAS1 mutations and aberrations in hypoxia signaling can provide insight into possible therapeutic strategies to preserve vision in these patients.

This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.

 

Representative funduscopic images (A) and fluorescein angiograms (B) from Epas1 mutation murine model mice showing fibrosis over the optic disc and leakage of fluorescein dye, respectively, when compared to littermate controls.