TY  - BOOK
AU  - Nazari, Matthew A
TI  - Developmental vascular malformations in EPAS1 gain-of-function syndrome
SN  - 2379-3708
PY  - 2021///
KW  - *Basic Helix-Loop-Helix Transcription Factors/ge [Genetics]
KW  - *Neuroendocrine Tumors/ge [Genetics]
KW  - *Polycythemia/ge [Genetics]
KW  - *Vascular Malformations/ge [Genetics]
KW  - Adolescent
KW  - Adult
KW  - Animals
KW  - Female
KW  - Gain of Function Mutation
KW  - Gene Expression Regulation
KW  - Humans
KW  - Male
KW  - Mice
KW  - Mice, Transgenic
KW  - Middle Aged
KW  - Young Adult
KW  - MedStar Washington Hospital Center
KW  - Internal Medicine & Pediatrics Residency
KW  - Journal Article
N2  - 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
UR  - https://dx.doi.org/10.1172/jci.insight.144368
ER  -