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Developmental vascular malformations in EPAS1 gain-of-function syndrome.

MedStar author(s):

2379-3708

Name of journal: JCI insightAbstract: Mutations in EPAS1, encoding hypoxia-inducible factor-2alpha (HIF-2alpha), were previously identified in a syndrome of multiple paragangliomas, somatostatinoma, and polycythemia. HIF-2alpha, when dimerized with HIF-1beta, acts as an angiogenic transcription factor. Patients referred to the NIH for new, recurrent, and/or metastatic paraganglioma or pheochromocytoma were confirmed for EPAS1 gain-of-function mutation; imaging was evaluated for vascular malformations. We evaluated the Epas1A529V transgenic syndrome mouse model, corresponding to the mutation initially detected in the patients (EPAS1A530V), for vascular malformations via intravital 2-photon microscopy of meningeal vessels, terminal vascular perfusion with Microfil silicate polymer and subsequent intact ex vivo 14T MRI and micro-CT, and histologic sectioning and staining of the brain and identified pathologies. Further, we evaluated retinas from corresponding developmental time points (P7, P14, and P21) and the adult dura via immunofluorescent labeling of vessels and confocal imaging. We identified a spectrum of vascular malformations in all 9 syndromic patients and in all our tested mutant mice. Patient vessels had higher variant allele frequency than adjacent normal tissue. Veins of the murine retina and intracranial dura failed to regress normally at the expected developmental time points. These findings add vascular malformation as a new clinical feature of EPAS1 gain-of-function syndrome.All authors: Cappadona AJ, Chew E, Dmitriev PM, Donahue DR, Edwards N, Gilbert MR, Heiss JD, Jha A, Knutsen RH, Kozel BA, Mastorakos P, McGavern DB, Munasinghe J, Nazari MA, Pacak K, Pappo A, Rosenblum BR, Rosenblum JS, Smirniotopoulos JG, Spetzler RF, Vortmeyer A, Wang H, Xu C, Zhuang ZOriginally published: Jci Insight. 6(5), 2021 Mar 08.Fiscal year: FY2021Fiscal year of original publication: FY2021Digital Object Identifier:

https://dx.doi.org/10.1172/jci.insight.144368

Date added to catalog: 2021-06-07

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Item type	Current library	Collection	Call number	Status	Date due	Barcode
Journal Article	MedStar Authors Catalog	Article	33497361	Available		33497361

Mutations in EPAS1, encoding hypoxia-inducible factor-2alpha (HIF-2alpha), were previously identified in a syndrome of multiple paragangliomas, somatostatinoma, and polycythemia. HIF-2alpha, when dimerized with HIF-1beta, acts as an angiogenic transcription factor. Patients referred to the NIH for new, recurrent, and/or metastatic paraganglioma or pheochromocytoma were confirmed for EPAS1 gain-of-function mutation; imaging was evaluated for vascular malformations. We evaluated the Epas1A529V transgenic syndrome mouse model, corresponding to the mutation initially detected in the patients (EPAS1A530V), for vascular malformations via intravital 2-photon microscopy of meningeal vessels, terminal vascular perfusion with Microfil silicate polymer and subsequent intact ex vivo 14T MRI and micro-CT, and histologic sectioning and staining of the brain and identified pathologies. Further, we evaluated retinas from corresponding developmental time points (P7, P14, and P21) and the adult dura via immunofluorescent labeling of vessels and confocal imaging. We identified a spectrum of vascular malformations in all 9 syndromic patients and in all our tested mutant mice. Patient vessels had higher variant allele frequency than adjacent normal tissue. Veins of the murine retina and intracranial dura failed to regress normally at the expected developmental time points. These findings add vascular malformation as a new clinical feature of EPAS1 gain-of-function syndrome.

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