title: 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: Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors: Qiulin
authors: Q
authors: Tan
authors: Heddy
authors: H
authors: Kerestes
authors: Melanie J
authors: MJ
authors: Percy
authors: Ralph
authors: R
authors: Pietrofesa
authors: Li
authors: L
authors: Chen
authors: Tejvir S
authors: TS
authors: Khurana
authors: Melpo
authors: M
authors: Christofidou-Solomidou
authors: Terence R J
authors: TR
authors: Lappin
authors: Frank S
authors: FS
authors: Lee
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics* / Q000378:metabolism; D001784:Blood Gas Analysis; D002478:Cells, Cultured; D004195:Disease Models, Animal; D019332:Endothelin-1 / Q000235:genetics / Q000378:metabolism; D004920:Erythropoiesis; D004921:Erythropoietin / Q000097:blood / Q000235:genetics; D015870:Gene Expression; D055879:Gene Knock-In Techniques; D056726:Genetic Association Studies; D006801:Humans; D006976:Hypertension, Pulmonary / Q000097:blood / Q000235:genetics* / Q000503:physiopathology; D017380:Hypertrophy, Right Ventricular / Q000097:blood / Q000235:genetics / Q000503:physiopathology; D007668:Kidney / Q000378:metabolism; D008168:Lung / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D016296:Mutagenesis; D020125:Mutation, Missense; D011086:Polycythemia / Q000097:blood / Q000235:genetics* / Q000503:physiopathology; D020574:Proto-Oncogene Proteins c-sis / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D056152:Respiratory Rate; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000097:blood; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D019332:Endothelin-1; D004921:Erythropoietin; D020574:Proto-Oncogene Proteins c-sis; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; D000099162:Endothelial PAS Domain-Containing Protein 1; C467480:vascular endothelial growth factor A, mouse
keywords: Erythropoietin; Hypoxia; Hypoxia Inducible Factor; Hypoxia-inducible Factor (HIF); Mouse
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