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Erythrocytosis and Pulmonary Hypertension in a Mouse Model of Human HIF2A Gain of Function Mutation*

Qiulin Tan,Heddy Kerestes,M. Percy,R. Pietrofesa,L. Chen,T. Khurana,M. Christofidou-Solomidou,T. Lappin,F. Lee

Published 2013 in Journal of Biological Chemistry

ABSTRACT

Background: Missense mutations have been identified in the HIF2A gene in patients with erythrocytosis. Results: A mouse knock-in line that models the first described HIF2A mutation exhibits erythrocytosis and pulmonary hypertension. Conclusion: The missense mutation is the cause of erythrocytosis, and is accompanied by pulmonary hypertension. Significance: The study demonstrates sequelae of global Hif-2α gain of function. The central pathway for oxygen-dependent control of red cell mass is the prolyl hydroxylase domain protein (PHD):hypoxia inducible factor (HIF) pathway. PHD site specifically prolyl hydroxylates the transcription factor HIF-α, thereby targeting the latter for degradation. Under hypoxia, this modification is attenuated, allowing stabilized HIF-α to activate target genes, including that for erythropoietin (EPO). Studies employing genetically modified mice point to Hif-2α, one of two main Hif-α isoforms, as being the critical regulator of Epo in the adult mouse. More recently, erythrocytosis patients with heterozygous point mutations in the HIF2A gene have been identified; whether these mutations were polymorphisms unrelated to the phenotype could not be ruled out. In the present report, we characterize a mouse line bearing a G536W missense mutation in the Hif2a gene that corresponds to the first such human mutation identified (G537W). We obtained mice bearing both heterozygous and homozygous mutations at this locus. We find that these mice display, in a mutation dose-dependent manner, erythrocytosis and pulmonary hypertension with a high degree of penetrance. These findings firmly establish missense mutations in HIF-2α as a cause of erythrocytosis, highlight the importance of this HIF-α isoform in erythropoiesis, and point to physiologic consequences of HIF-2α dysregulation.

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