A novel erythrocytosis-associated PHD2 mutation suggests the location of a HIF binding groove.

A novel erythrocytosis-associated PHD2 mutation suggests the location of a HIF binding groove Running title: Erythrocytosis and the PHD2 Arg371His mutation

Erythrocytosis associated with a novel missense mutation in the HIF2A gene.

The ERYTHROPOIETIN (EPO) gene is regulated by the transcription factor Hypoxia Inducible Factor-alpha (HIF-alpha). In this pathway, Prolyl Hydroxylase Domain protein 2 (PHD2) hydroxylates two prolyl residues in HIF-alpha, which in turn promotes HIF-alpha degradation by the von Hippel Lindau (VHL) protein. Evidence that HIF-2alpha is the important isoform for EPO regulation in humans comes from ...

Isolated erythrocytosis: study of 67 patients and identification of three novel germ-line mutations in the prolyl hydroxylase domain protein 2 (PHD2) gene.

The oxygen sensing pathway modulates erythropoietin expression. In normal cells, intracellular oxygen tensions are directly sensed by prolyl hydroxylase domain (PHD)-containing proteins. PHD2 isozyme has a key role in tagging hypoxia-inducible factor (HIF)-α subunits for polyubiquitination and proteasomal degradation. Erythrocytosis-associated PHD2 mutations reduce hydroxylation of HIF-α. The i...

Familial erythrocytosis arising from a gain-of-function mutation in the HIF2A gene of the oxygen sensing pathway

A mutation of HIF-2 alpha has been detected in three generations of a family with erythrocytosis and the mutation co-segregated with the erythrocytosis phenotype. Functional studies revealed that Gly537Trp mutation would significantly impair the function of HIF-2 alpha thus leading to increased synthesis of Epo. In addition to VHL and PHD2 a further member of the oxygen sensing pathway, namely ...

Regulation of adult erythropoiesis by prolyl hydroxylase domain proteins.

Polycythemia is often associated with erythropoietin (EPO) overexpression and defective oxygen sensing. In normal cells, intracellular oxygen concentrations are directly sensed by prolyl hydroxylase domain (PHD)-containing proteins, which tag hypoxia-inducible factor (HIF) alpha subunits for polyubiquitination and proteasomal degradation by oxygen-dependent prolyl hydroxylation. Here we show th...