RGD Reference Report - A knock-in mouse model of human PHD2 gene-associated erythrocytosis establishes a haploinsufficiency mechanism. - Rat Genome Database

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A knock-in mouse model of human PHD2 gene-associated erythrocytosis establishes a haploinsufficiency mechanism.

Authors: Arsenault, PR  Pei, F  Lee, R  Kerestes, H  Percy, MJ  Keith, B  Simon, MC  Lappin, TR  Khurana, TS  Lee, FS 
Citation: Arsenault PR, etal., J Biol Chem. 2013 Nov 22;288(47):33571-84. doi: 10.1074/jbc.M113.482364. Epub 2013 Oct 11.
RGD ID: 11251767
Pubmed: PMID:24121508   (View Abstract at PubMed)
PMCID: PMC3837105   (View Article at PubMed Central)
DOI: DOI:10.1074/jbc.M113.482364   (Journal Full-text)

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.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
polycythemia  ISOEgln1 (Mus musculus)11251767; 11251767 RGD 
polycythemia  IMP 11251767 RGD 

Objects Annotated

Genes (Rattus norvegicus)
Egln1  (egl-9 family hypoxia-inducible factor 1)

Genes (Mus musculus)
Egln1  (egl-9 family hypoxia-inducible factor 1)

Genes (Homo sapiens)
EGLN1  (egl-9 family hypoxia inducible factor 1)


Additional Information