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

We previously identified a novel syndrome in patients characterized by the presence of paraganglioma, somatostatinoma, and polycythemia. In these patients, polycythemia is observed long before any tumors develop, and removal of the tumors only partially resolves the condition, with recurrence occurring shortly after surgery. Genetic mosaicism of gain-of-function mutations in the EPAS1 gene (encoding HIF2α), specifically in the oxygen degradation domain (ODD) at positions p.530-532, was identified as the underlying cause of this syndrome. The objective of the current study was to establish that these mutations are both necessary and sufficient for the development of the syndrome’s symptoms.

To achieve this, we developed transgenic mice carrying a gain-of-function Epas1A529V mutation, which corresponds to the human EPAS1A530V mutation. These mice exhibited elevated levels of erythropoietin and developed polycythemia, displayed a decreased urinary metanephrine-to-normetanephrine ratio, and showed increased expression of somatostatin in the ampullary region of the duodenum. Treatment with PT2385, a specific inhibitor of HIF2α, significantly reduced erythropoietin levels in the mutant mice. However, polycythemia persisted despite PT2385 treatment, indicating the existence of an erythropoietin-independent mechanism contributing to the condition.

These findings confirm the critical role of EPAS1 mutations in the development of the syndrome and highlight the potential of the Epas1A529V animal model for advancing research into the pathogenesis and therapeutic options for this condition.