Abstract
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.
Highlights
Missense mutations have been identified in the HIF2A gene in patients with erythrocytosis
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 recently identified a heterozygous gain of function missense mutation in the HIF2A gene associated with erythrocytosis (19)
Summary
Missense mutations have been identified in the HIF2A gene in patients with erythrocytosis. Studies employing genetically modified mice have identified Hif-2␣ as being the critical isoform (16 –18) These studies lead to the question of whether human mutations in HIF genes might be associated with erythrocytosis. We recently identified a heterozygous gain of function missense mutation in the HIF2A gene associated with erythrocytosis (19) This mutation, G537W, is in the vicinity of the primary site of hydroxylation. Additional mutations in the HIF2A gene associated with erythrocytosis have subsequently been identified (20 –23) These mutations are all heterozygous missense mutations that change amino acids that are in close proximity to the primary site of hydroxylation, Pro-531. This model provides an opportunity to test whether a single amino acid change in Hif-2␣ is sufficient to induce erythrocytosis, and examine whether there are other sequelae from this global dysregulation of Hif-2␣ function
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