Erythrocytosis Associated with a Novel Missense Mutation in the HIF2A Gene

Overview

Journal Haematologica

Specialty Hematology

Date 2009 Dec 17

PMID 20007141

Citations 20

Authors

Richard van Wijk

Scott Sutherland

Annet C W van Wesel

Eric G Huizinga

Melanie J Percy

Marc Bierings

Frank S Lee

Affiliations

Soon will be listed here.

Abstract

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 the recent observation that mutations in the HIF2A gene are associated with cases of erythrocytosis. We report here a new erythrocytosis-associated mutation, p.Asp539Glu, in the HIF2A gene. Similar to all reported cases, the affected residue is in close vicinity and C-terminal to the primary hydroxylation site in HIF-2alpha, Pro531. This mutation, however, is notable in producing a rather subtle amino acid substitution. Nonetheless, we find that this mutation compromises binding of HIF-2alpha to both PHD2 and VHL, and we propose that this mutation is the cause of erythrocytosis in this individual.

Citing Articles

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