Novel exon 12 mutations in the HIF2A gene associated with erythrocytosis.
Erythrocytosis can arise from deregulation of the erythropoietin (Epo) axis resulting from defects in the oxygen-sensing pathway. Epo synthesis is controlled by the hypoxia inducible factor (HIF) complex, composed of an alpha and a beta subunit. There are 2 main alpha subunits, HIF-1 alpha and HIF-2 alpha. Recently, a HIF-2 alpha Gly537Trp mutation was identified in a family with erythrocytosis. This raises the possibility of HIF2A mutations being associated with other cases of erythrocytosis. We now report a subsequent analysis of HIF2A in a cohort of 75 erythrocytosis patients and identify 4 additional patients with novel heterozygous Met535Val and Gly537Arg mutations. All patients presented at a young age with elevated serum Epo. Mutations at Gly-537 account for 4 of 5 HIF2A mutations associated with erythrocytosis. These findings support the importance of HIF-2 alpha in human Epo regulation and warrant investigation of HIF2A in patients with unexplained erythrocytosis.
Percy
Melanie J
MJ
Department of Haematology, Belfast City Hospital, Belfast, United Kingdom. melanie.percy@belfasttrust.hscni.net
Beer
Philip A
PA
Campbell
Gavin
G
Dekker
Ad W
AW
Green
Anthony R
AR
Oscier
David
D
Rainey
M Glenn
MG
van Wijk
Richard
R
Wood
Marion
M
Lappin
Terence R J
TR
McMullin
Mary Frances
MF
Lee
Frank S
FS
D000293:Adolescent; D000328:Adult; D001483:Base Sequence; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics*; D004252:DNA Mutational Analysis; D004921:Erythropoietin / Q000097:blood; D005260:Female; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D011086:Polycythemia / Q000235:genetics*; D016133:Polymerase Chain Reaction; D000099162:Endothelial PAS Domain-Containing Protein 1
D051792:Basic Helix-Loop-Helix Proteins; D004921:Erythropoietin; D000099162:Endothelial PAS Domain-Containing Protein 1