title: Erythrocytosis associated with a novel missense mutation in the HIF2A gene.
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.
authors.affiliation: Laboratory for Red Blood Cell Research, Department of Clinical Chemistry and Haematology, University Medical Center Utrecht, Utrecht, the Netherlands.
authors.forename: Richard
authors.initials: R
authors.lastname: van Wijk
authors.forename: Scott
authors.initials: S
authors.lastname: Sutherland
authors.forename: Annet C W
authors.initials: AC
authors.lastname: Van Wesel
authors.forename: Eric G
authors.initials: EG
authors.lastname: Huizinga
authors.forename: Melanie J
authors.initials: MJ
authors.lastname: Percy
authors.forename: Marc
authors.initials: M
authors.lastname: Bierings
authors.forename: Frank S
authors.initials: FS
authors.lastname: Lee
mesh_terms: D000293:Adolescent; D051792:Basic Helix-Loop-Helix Proteins / Q000737:chemistry / Q000235:genetics*; D005260:Female; D006801:Humans; D020125:Mutation, Missense / Q000235:genetics*; D011086:Polycythemia / Q000175:diagnosis* / Q000235:genetics*; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D000099162:Endothelial PAS Domain-Containing Protein 1