TY - JOUR
T1 - Erythrocytosis associated with a novel missense mutation in the HIF2A gene
AU - van Wijk, R.
AU - Sutherland, S.
AU - van Wesel, A.C.W.
AU - Huizinga, E.G.
AU - Percy, M.J.
AU - Bierings, M.B.
AU - Lee, F.S.
PY - 2010
Y1 - 2010
N2 - 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.
AB - 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.
U2 - 10.3324/haematol.2009.017582
DO - 10.3324/haematol.2009.017582
M3 - Article
SN - 0390-6078
VL - 95
SP - 829
EP - 832
JO - Haematologica-The Hematology Journal
JF - Haematologica-The Hematology Journal
IS - 5
ER -