Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Case Reports
. 2008 Jun 1;111(11):5400-2.
doi: 10.1182/blood-2008-02-137703. Epub 2008 Mar 31.

Novel exon 12 mutations in the HIF2A gene associated with erythrocytosis

Melanie J Percy  1 , Philip A Beer, Gavin Campbell, Ad W Dekker, Anthony R Green, David Oscier, M Glenn Rainey, Richard van Wijk, Marion Wood, Terence R J Lappin, Mary Frances McMullin, Frank S Lee
Affiliations
Case Reports

Novel exon 12 mutations in the HIF2A gene associated with erythrocytosis

Melanie J Percy et al. Blood. .

Abstract

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.

PubMed Disclaimer

Figures

Figure 1
Figure 1
Identification of the c.1603A>G and c.1609G>A mutations in the HIF2A gene. (A) Detection of the c.1603A>G and c.1609G>A mutations by PCR-direct sequencing. PCR was performed on total peripheral blood DNA using a set of primers to specifically amplify exon 12 of the HIF2A gene. Sequencing detected a heterozygous A to G change at base 1603 in patient H2 (middle panel) and G to A at base 1609 in patient H5 (bottom panel) as indicated by arrows compared with wild-type sequence (top panel). Shown are nucleotides 1587 to 1615. Bases are as follows: G, black; A, green; T, red; C, blue. (B) Three-dimensional structure of the VHL:ElonginC:ElonginB complex bound to hydroxyproline-564 HIF-1α peptide (residues 556-575). The structure was generated using Cn3D from PDB coordinates (1LM8) deposited by Min et al. The positions of hydroxyproline-564 (Hyp-564), Met-568, and Asp-570 are shown (all in bright yellow). The sequences of HIF-2α and HIF-1α at the primary hydroxylation site are compared, with the corresponding HIF-2α residues indicated.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Semenza GL. Life with oxygen. Science. 2007;318:62–64. - PubMed
    1. Ivan M, Kondo K, Yang H, et al. HIFalpha targeted for VHL-mediated destruction by proline hydroxylation: implications for O2 sensing. Science. 2001;292:464–468. - PubMed
    1. Jaakkola P, Mole DR, Tian YM, et al. Targeting of HIF-alpha to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation. Science. 2001;292:468–472. - PubMed
    1. Yu F, White SB, Zhao Q, Lee FS. HIF-1alpha binding to VHL is regulated by stimulus-sensitive proline hydroxylation. Proc Natl Acad Sci U S A. 2001;98:9630–9635. - PMC - PubMed
    1. Epstein AC, Gleadle JM, McNeill LA, et al. C. elegans EGL-9 and mammalian homologs define a family of dioxygenases that regulate HIF by prolyl hydroxylation. Cell. 2001;107:43–54. - PubMed

Publication types

Substances