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Developmental vascular malformations in EPAS1 gain-of-function syndrome
- Source :
- JCI Insight, JCI Insight, Vol 6, Iss 5 (2021)
- Publication Year :
- 2021
- Publisher :
- American Society for Clinical Investigation, 2021.
-
Abstract
- Mutations in EPAS1, encoding hypoxia-inducible factor-2α (HIF-2α), were previously identified in a syndrome of multiple paragangliomas, somatostatinoma, and polycythemia. HIF-2α, when dimerized with HIF-1β, 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.<br />We discovered vascular malformations due to failure of developmental vascular regression in patients with EPAS1 gain-of-function mutation syndrome and the corresponding transgenic mouse model.
- Subjects :
- 0301 basic medicine
Adult
Male
Pathology
medicine.medical_specialty
Adolescent
Angiogenesis
Vascular Malformations
Mice, Transgenic
Polycythemia
Development
Mouse models
Pheochromocytoma
03 medical and health sciences
Mice
Young Adult
0302 clinical medicine
Paraganglioma
medicine
Basic Helix-Loop-Helix Transcription Factors
Animals
Humans
Retina
business.industry
Vascular malformation
General Medicine
Somatostatinoma
Middle Aged
medicine.disease
Neuroendocrine Tumors
030104 developmental biology
medicine.anatomical_structure
Gene Expression Regulation
030220 oncology & carcinogenesis
Gain of Function Mutation
Medicine
Female
business
Perfusion
Ex vivo
Research Article
Genetic diseases
Subjects
Details
- Language :
- English
- ISSN :
- 23793708
- Volume :
- 6
- Issue :
- 5
- Database :
- OpenAIRE
- Journal :
- JCI Insight
- Accession number :
- edsair.doi.dedup.....da56750d422db54ef28fdeb7603c2c8f