ArticleThe Journal of biological chemistry2013
A knock-in mouse model of human PHD2 gene-associated erythrocytosis establishes a haploinsufficiency mechanism.
Article in The Journal of biological chemistry, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 35 papers.
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Who cites it
35 citing papers in PubMed, 53 citations in OpenAlex.
- Article
- Genetic modifications ofHeliyon · 2024Article
- PHD1-3 oxygen sensors in vivo-lessons learned from gene deletions.Pflugers Archiv : European journal of physiology · 2024Review
- Characterization of genetic variants in theHaematologica · 2023Article
- Pacak-Zhuang syndrome: a model providing new insights into tumor syndromes.Endocrine-related cancer · 2023Review
- High-Altitude Andean H194R HIF2A Allele Is a Hypomorphic Allele.Molecular biology and evolution · 2023Article
- The ribosomal chaperone NACA recruits PHD2 to cotranslationally modify HIF-α.The EMBO journal · 2022Article
- Article
- Genetic Background of Congenital Erythrocytosis.Genes · 2021Review
- High-Altitude Adaptation: Mechanistic Insights from Integrated Genomics and Physiology.Molecular biology and evolution · 2021Review
- Hypoxia Pathway Proteins are Master Regulators of Erythropoiesis.International journal of molecular sciences · 2020Review
- The pVHL neglected functions, a tale of hypoxia-dependent and -independent regulations in cancer.Open biology · 2020Review
- TibetanProceedings of the National Academy of Sciences of the United States of America · 2020Article
- Diagnostic workflow for hereditary erythrocytosis and thrombocytosis.Hematology. American Society of Hematology. Education Program · 2019Review
- Association ofProceedings of the National Academy of Sciences of the United States of America · 2019Article
- Update on mutations in the HIF: EPO pathway and their role in erythrocytosis.Blood reviews · 2019Review
- Loss of Phd2 cooperates with BRAFNature communications · 2018Article
- PHD2 inactivation in Type I cells drives HIF-2α-dependent multilineage hyperplasia and the formation of paraganglioma-like carotid bodies.The Journal of physiology · 2018Article
- VHL and Hypoxia Signaling: Beyond HIF in Cancer.Biomedicines · 2018Review
- Hypoxia-Inducible Factor and Its Role in the Management of Anemia in Chronic Kidney Disease.International journal of molecular sciences · 2018Review
Corrections and comments
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Authors and funding
10 authors at 4 institutions in 2 countries.
Funding
Abstract
The central pathway for controlling red cell mass is the PHD (prolyl hydroxylase domain protein):hypoxia-inducible factor (HIF) pathway. HIF, which is negatively regulated by PHD, activates numerous genes, including ones involved in erythropoiesis, such as the ERYTHROPOIETIN (EPO) gene. Recent studies have implicated PHD2 as the key PHD isoform regulating red cell mass. Studies of humans have identified erythrocytosis-associated, heterozygous point mutations in the PHD2 gene. A key question concerns the mechanism by which human mutations lead to phenotypes. In the present report, we generated and characterized a mouse line in which a P294R knock-in mutation has been introduced into the mouse Phd2 locus to model the first reported human PHD2 mutation (P317R). Phd2(P294R/+) mice display a degree of erythrocytosis equivalent to that seen in Phd2(+/-) mice. The Phd2(P294R/+)-associated erythrocytosis is reversed in a Hif2a(+/-), but not a Hif1a(+/-) background. Additional studies using various conditional knock-outs of Phd2 reveal that erythrocytosis can be induced by homozygous and heterozygous knock-out of Phd2 in renal cortical interstitial cells using a Pax3-Cre transgene or by homozygous knock-out of Phd2 in hematopoietic progenitors driven by a Vav1-Cre transgene. These studies formally prove that a missense mutation in PHD2 is the cause of the erythrocytosis, show that this occurs through haploinsufficiency, and point to multifactorial control of red cell mass by PHD2.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.