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HIF-2 alpha plays key role in erythropoietin production
Previous research suggested greater role for hypoxia inducible factor-1.
ATLANTA — Erythropoietin production in humans may be controlled by hypoxia inducible factor-2 alpha, according to a late breaking trial presented at the 49th American Society of Hematology Annual Meeting and Exposition.
“Previous studies in mice have suggested that HIF-2 alpha plays a critical role, but this is the first time it has been confirmed in humans,” said Melanie J. Percy, PhD, a hematologist at Belfast City Hospital in Northern Ireland.
Red cell homeostasis is crucial to maintain a sustained tissue oxygen supply. Red cell production is stimulated by renal erythropoietin after oxygen is sensed by the kidneys, which then induce hypoxia.
At this molecular level, the process is controlled by hypoxia inducible factor complex, which includes a labile alpha subunit and a constitutively expressed beta subunit.
Key prolines present in the oxygen-dependent degradation domain of the alpha subunit are hydroxylated by prolyl hydroxase domain proteins. After hydroxylation, the von Hippel Lindau protein binds and targets hypoxia inducible factor to the proteosome.
Genetic mutations
Each isoform of hypoxia inducible factor shows differential tissue distribution, and they exhibit diverse affinities for the hypoxia response elements located in the promoters and enhancers of the hypoxia inducible factor target genes.
Identification of which hypoxia inducible factor is clinically relevant because dysregulation of erythropoietin production can give rise to erythrocytosis. Defects in the oxygen sensing pathway can lead to this disorder.
In their analysis, Percy and colleagues observed that after sequencing HIF-2 alpha, a novel heterozygous c.G1609T mutation was uncovered in three generations of one family with erythrocytosis.
“All of the affected individuals in this family exhibited greatly elevated serum erythropoietin levels,” Percy said.
However, among the family members who were not affected by erythrocytosis, the c.G1609T mutation was absent. A similar absence was observed in 200 healthy control patients.
Percy said the c.G1609T mutation predicts the replacement of Gly by Trp at amino acid 537, which is close to the main site of proline hydroxylation at 531.
Subsequent functional assays confirmed that the Gly537Trp variant was less hydroxylated and exhibited a reduced affinity for the von Hippel Lindau protein, which targets HIF-A alpha for proteasomal degradation.
Furthermore, according to the research abstract, the increased stability in normoxia of the Gly537Trp variant would result in elevated transcription of HIF-2 target genes.
“Consequently, these findings support a critical role for HIF-2 alpha in the control of erythropoietin production in humans,” Percy said. –by Jeremy Moore
For more information:
- Percy MJ, Furlow PW, Lucas GS, et al. A novel HIFalpha mutation associated with familial erythrocytosis supports this isoform being the major regulator of erythropoietin in humans. #LB5. Presented at: 49th American Society of Hematology Annual Meeting and Exposition; Dec. 8-11, 2007; Atlanta.