Erythrocytosis associated with a novel missense mutation in the HIF2A gene

R. van Wijk, S. Sutherland, A.C.W. van Wesel, E.G. Huizinga, M.J. Percy, M.B. Bierings, F.S. Lee

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

The ERYTHROPOIETIN (EPO) gene is regulated by the transcription factor Hypoxia Inducible Factor- (HIF-). In this pathway, Prolyl Hydroxylase Domain protein 2 (PHD2) hydroxylates two prolyl residues in HIF-, which in turn promotes HIF- degradation by the von Hippel Lindau (VHL) protein. Evidence that HIF-2 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-2, Pro531. This mutation, however, is notable in producing a rather subtle amino acid substitution. Nonetheless, we find that this mutation compromises binding of HIF-2 to both PHD2 and VHL, and we propose that this mutation is the cause of erythrocytosis in this individual.
Original languageEnglish
Pages (from-to)829-832
Number of pages4
JournalHaematologica
Volume95
Issue number5
Publication statusPublished - 2010

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