Novel exon 12 mutations in the HIF2A gene associated with erythrocytosis

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

doi:10.1182/blood-2008-02-137703

Cited by 127Erythropoietin and Anemia TreatmentCancer, Hypoxia, and MetabolismHemoglobinopathies and Related Disorders

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Novel exon 12 mutations in the HIF2A gene associated with erythrocytosis

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Percy, Melanie J., Beer, Philip A., Campbell, Gavin, Dekker, Ad W., Green, Anthony R., Oscier, David, Rainey, M. Glenn, van Wijk, Richard, Wood, Marion, Lappin, Terence R. J., McMullin, Mary Frances, Lee, Frank S.·2008·Blood

DOI 10.1182/blood-2008-02-137703PMC PMC2396730

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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.

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Most gain-of-function mutations in HIF-2α are in direct proximity to proline residue 531.
“Most gain-of-function mutations in HIF-2α are in direct proximity to proline residue 531, which is one of the two main hydroxylation sites (the other major hydroxylation site is proline 405). 147–154”
From Regulation of erythropoiesis by hypoxia-inducible factors (2013) · cites this paper as [148]

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Two new mutations in the HIF2A gene associated with erythrocytosis
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A novel heterozygous HIF2AM535I mutation reinforces the role of oxygen sensing pathway disturbances in the pathogenesis of familial erythrocytosis
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Authors: Percy, M. J., Beer, P. A., Campbell, G., Dekker, A. W., Green, A. R., Oscier, D., Rainey, M. G., van Wijk, R., Wood, M., Lappin, T. R. J., McMullin, M. F., & Lee, F. S.
Affiliations: Belfast City Hospital (GB)
University of Cambridge (GB)
National Health Service (GB)
University Medical Center Utrecht (NL)
Royal Bournemouth Hospital (GB)
Vale of Leven District General Hospital (GB)
Department of Clinical Chemistry and Hematology, University Medical Center Utrecht, Utrecht, The Netherlands;
Queen's University Belfast (GB)
University of Pennsylvania (US)
ORCID: Beer, Philip A.
Green, Anthony R.
Oscier, David
Wood, Marion
Lappin, Terence R. J.
McMullin, Mary Frances
Lee, Frank S.
Venue: Blood
Publisher: American Society of Hematology
Published: 2008-06-01
Volume: 111
Issue: 11
Pages: 5400-5402
ISSN: 0006-4971 (ISSN-L)
1528-0020
DOI: 10.1182/blood-2008-02-137703
PMC: PMC2396730
OpenAlex: W2028331311
Cited by: 127
References: 21
Citations by year: 2026: 2 · 2025: 1 · 2024: 7 · 2023: 6 · 2022: 3 · 2021: 8 · 2020: 1 · 2019: 6 · 2018: 4 · 2017: 4 · 2016: 11 · 2015: 4 · 2014: 9 · 2013: 18 · 2012: 4
FWCI: 8.22
Type: journal article
Language: en
Open access: green
europepmc.org
Locations: Blood (publishedVersion)
Europe PMC (PubMed Central) (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Research Portal (Queen's University Belfast) (submittedVersion)
Funders: Cancer Research UK
National Institutes of Health
National Cancer Institute (R01CA090261)
Topics: Health Sciences › Medicine › Hematology › Erythropoietin and Anemia Treatment
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
Health Sciences › Medicine › Genetics (clinical) › Hemoglobinopathies and Related Disorders
Keywords: erythrocytosis, HIF-2α, erythropoietin regulation, hypoxia-inducible factor, HIF-1α, oxygen sensing, serum erythropoietin
MeSH terms: Endothelial PAS Domain-Containing Protein 1, Adolescent, Adult, Base Sequence, DNA Mutational Analysis, Erythropoietin, Female, Humans, Male, Molecular Sequence Data, Mutation, Polycythemia, Polymerase Chain Reaction, Basic Helix-Loop-Helix Proteins

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Novel exon 12 mutations in the HIF2A gene associated with erythrocytosis

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