Erythrocytosis and pulmonary hypertension in a mouse model of human HIF2A gain of function mutation.

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.

• Authors: Qiulin Tan, Heddy Kerestes, Melanie J Percy, Ralph Pietrofesa, Li Chen, Tejvir S Khurana, Melpo Christofidou-Solomidou, Terence R J Lappin, Frank S Lee
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 288 Issue 24 Pg. 17134-44 (Jun 14 2013) ISSN: 1083-351X [Electronic] United States
• PMID: 23640890 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Basic Helix-Loop-Helix Transcription Factors
• Endothelin-1
• Proto-Oncogene Proteins c-sis
• RNA, Messenger
• Vascular Endothelial Growth Factor A
• vascular endothelial growth factor A, mouse
• Erythropoietin
• endothelial PAS domain-containing protein 1

Topics

• Animals
• Basic Helix-Loop-Helix Transcription Factors (genetics, metabolism)
• Blood Gas Analysis
• Cells, Cultured
• Disease Models, Animal
• Endothelin-1 (genetics, metabolism)
• Erythropoiesis
• Erythropoietin (blood, genetics)
• Gene Expression
• Gene Knock-In Techniques
• Genetic Association Studies
• Humans
• Hypertension, Pulmonary (blood, genetics, physiopathology)
• Hypertrophy, Right Ventricular (blood, genetics, physiopathology)
• Kidney (metabolism)
• Lung (metabolism, pathology, physiopathology)
• Mice
• Mice, Inbred C57BL
• Mutagenesis
• Mutation, Missense
• Polycythemia (blood, genetics, physiopathology)
• Proto-Oncogene Proteins c-sis (genetics, metabolism)
• RNA, Messenger (genetics, metabolism)
• Respiratory Rate
• Up-Regulation
• Vascular Endothelial Growth Factor A (blood)