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A Transgenic Mouse Model of Pacak–Zhuang Syndrome with An Epas1 Gain-of-Function Mutation

Neuro-Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA
Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA
Surgical Neurology Branch, National Institute of Neurological Diseases and Stroke, National Institutes of Health, Bethesda, MD 20892, USA
Institute of Clinical Chemistry and Laboratory Medicine and Department of Medicine III, University Hospital Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany
Authors to whom correspondence should be addressed.
Cancers 2019, 11(5), 667;
Received: 28 March 2019 / Revised: 7 May 2019 / Accepted: 10 May 2019 / Published: 14 May 2019
(This article belongs to the Special Issue Pheochromocytoma (PHEO) and Paraganglioma (PGL))
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We previously identified a novel syndrome in patients characterized by paraganglioma, somatostatinoma, and polycythemia. In these patients, polycythemia occurs long before any tumor develops, and tumor removal only partially corrects polycythemia, with recurrence occurring shortly after surgery. Genetic mosaicism of gain-of-function mutations of the EPAS1 gene (encoding HIF2α) located in the oxygen degradation domain (ODD), typically p.530–532, was shown as the etiology of this syndrome. The aim of the present investigation was to demonstrate that these mutations are necessary and sufficient for the development of the symptoms. We developed transgenic mice with a gain-of-function Epas1A529V mutation (corresponding to human EPAS1A530V), which demonstrated elevated levels of erythropoietin and polycythemia, a decreased urinary metanephrine-to-normetanephrine ratio, and increased expression of somatostatin in the ampullary region of duodenum. Further, inhibition of HIF2α with its specific inhibitor PT2385 significantly reduced erythropoietin levels in the mutant mice. However, polycythemia persisted after PT2385 treatment, suggesting an alternative erythropoietin-independent mechanism of polycythemia. These findings demonstrate the vital roles of EPAS1 mutations in the syndrome development and the great potential of the Epas1A529V animal model for further pathogenesis and therapeutics studies. View Full-Text
Keywords: paraganglioma; somatostatinoma; polycythemia; EPAS1; transgenic mice; erythropoietin paraganglioma; somatostatinoma; polycythemia; EPAS1; transgenic mice; erythropoietin

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Wang, H.; Cui, J.; Yang, C.; Rosenblum, J.S.; Zhang, Q.; Song, Q.; Pang, Y.; Fang, F.; Sun, M.; Dmitriev, P.; Gilbert, M.R.; Eisenhofer, G.; Pacak, K.; Zhuang, Z. A Transgenic Mouse Model of Pacak–Zhuang Syndrome with An Epas1 Gain-of-Function Mutation. Cancers 2019, 11, 667.

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