A Gain-of-Function Mutation in the HIF2A Gene in Familial Erythrocytosis
Open accessAbstract
Hypoxia-inducible factor (HIF) alpha, which has three isoforms, is central to the continuous balancing of the supply and demand of oxygen throughout the body. HIF-alpha is a transcription factor that modulates a wide range of processes, including erythropoiesis, angiogenesis, and cellular metabolism. We describe a family with erythrocytosis and a mutation in the HIF2A gene, which encodes the HIF-2alpha protein. Our functional studies indicate that this mutation leads to stabilization of the HIF-2alpha protein and suggest that wild-type HIF-2alpha regulates erythropoietin production in adults.
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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 [147]
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Hypoxia Pathway Proteins are Master Regulators of Erythropoiesis
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Uremic Toxins Affect Erythropoiesis during the Course of Chronic Kidney Disease: A Review
Hamza, E., Metzinger, L., & Meuth, V. M. (2020) · Cells · doi:10.3390/cells9092039 · Cited by 77 · see citing works
Defective Tibetan PHD2 Binding to p23 Links High Altitude Adaption to Altered Oxygen Sensing
Song, D., Li, L.-S., Arsenault, P. R., Tan, Q., Bigham, A. W., Heaton-Johnson, K. J., Master, S. R., & Lee, F. S. (2014) · Journal of Biological Chemistry · doi:10.1074/jbc.m113.541227 · Cited by 80 · see citing works
Self-citationFranke, K., Kalucka, J. M., Mamlouk, S., Singh, R. P., Muschter, A., Weidemann, A., Iyengar, V., Jahn, S., Wieczorek, K. S., Geiger, K. D., et al. (2012) · Blood · doi:10.1182/blood-2012-08-449181 · Cited by 83 · see citing works
Update on mutations in the HIF: EPO pathway and their role in erythrocytosis
Lappin, T. R. J., & Lee, F. S. (2019) · Blood Reviews · doi:10.1016/j.blre.2019.100590 · Cited by 82 · see citing works
“The first erythrocytosisassociated mutation in the pathway was identified in the VHL gene [20] followed by a mutation in the PHD2 gene [21] and subsequently by a mutation of the HIF2A (also known as EPAS1) gene in a family with hereditary erythrocytosis [22].”
BackgroundSelf-citationRussell, R. C., Sufan, R. I., Zhou, B. R., Heir, P., Bunda, S., Sybingco, S. S., Greer, S. N., Roche, O., Heathcote, S. A., Chow, V. W. K., et al. (2011) · Nature Medicine · doi:10.1038/nm.2370 · Cited by 78 · see citing works
Investigation and Management of Erythrocytosis
McMullin, M. F. (2016) · Current Hematologic Malignancy Reports · doi:10.1007/s11899-016-0334-1 · Cited by 49 · see citing works
Self-citationDiabetic nephropathy: a disorder of oxygen metabolism?
Miyata, T., & de Strihou, C. V. Y. (2009) · Nature Reviews Nephrology · doi:10.1038/nrneph.2009.211 · Cited by 85 · see citing works
Prediction of disease-related mutations affecting protein localization
Laurila, K., & Vihinen, M. (2009) · BMC Genomics · doi:10.1186/1471-2164-10-122 · Cited by 75 · see citing works
“Most mutations reduce protein activity, but increasing numbers of gain-of-function mutations [16,17] are also being identified.”
BackgroundMartini, M., Teofili, L., Cenci, T., Giona, F., Torti, L., Rea, M., Foa, R., Leone, G., & Larocca, L. M. (2008) · Haematologica · doi:10.3324/haematol.13210 · Cited by 73 · see citing works
“highlighted that also gain-of-function mutations of HIF2A gene cause hereditary erythrocytosis.(12,13) In this study we report a novel mutation of the HIF2A gene in 2 members of a familiy affected by idiopathic erythrocytosis.”
BackgroundInfluentialHIF prolyl hydroxylase inhibitors for anemia
Muchnik, E., & Kaplan, J. (2011) · Expert Opinion on Investigational Drugs · doi:10.1517/13543784.2011.566861 · Cited by 76 · see citing works
“Various analyses have indicated that HIF-2a is the prime factor in the regulation of renal erythropoietin (Epo) synthesis [17-24] and thus is the primary HIF molecule in the response to anemia.”
BackgroundInterplay of Hypoxia and A2B Adenosine Receptors in Tissue Protection
Koeppen, M., Eckle, T. D. L. G., & Eltzschig, H. K. (2011) · Advances in pharmacology · doi:10.1016/b978-0-12-385526-8.00006-0 · Cited by 73 · see citing works
Systems biology of oxygen homeostasis
Samanta, D., Prabhakar, N. R., & Semenza, G. L. (2017) · WIREs Systems Biology and Medicine · doi:10.1002/wsbm.1382 · Cited by 81 · see citing works
“Finally, missense mutations that result in the substitution of evolutionarily conserved residues (M535V, M535I, G537W, and G537R) in HIF-2α that are located near a proline residue that is subject to hydroxylation (Pro-532), suggesting that the substitutions reduce the efficiency with which the hydroxylases modify the…”
BackgroundDiabetic nephropathy: are there new and potentially promising therapies targeting oxygen biology?
Miyata, T., Suzuki, N., & de Strihou, C. V. Y. (2013) · Kidney International · doi:10.1038/ki.2013.74 · Cited by 88 · see citing works
Hypoxic regulation of mRNA expression
Gardner, L. B., & Corn, P. (2008) · Cell Cycle · doi:10.4161/cc.7.13.6203 · Cited by 69 · see citing works
“76 77-80 Mutations in succinate dehyrogenase and fumarate hyroxylase, which lead to increases in intermediaries that act as B I O S C I N competitive inhibitors of prolyl hydroxylase, lead to increase HIF-1 activity and hereditary cancer syndromes 81 The fact that erythropoietin (a HIF target) and erythropoiesis are i…”
BackgroundInfluentialErythropoietinPreprint
Bunn, H. F. (2013) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a011619 · Cited by 247 · see citing works
“…as well as isolated individuals have been encountered in which erythrocytosis owing to elevated plasma Epo levels is explained by heterozygosity for an activating mutation in HIF-2a (Gale et al. 2008; Martini et al. 2008; Percy et al. 2008a,b, 2012; Furlow et al. 2009; van Wijk et al. 2010).”
BackgroundNovel insights into the polycythemia–paraganglioma–somatostatinoma syndrome
Därr, R., Nambuba, J., Rivero, J. D., Janssen, I., Merino, M. J., Todorović, M., Balint, B., Jochmanová, I., Prchal, J. T., Lechan, R. M., et al. (2016) · Endocrine Related Cancer · doi:10.1530/erc-16-0231 · Cited by 84 · see citing works
“2008, Gale et al. 2008, Percy et al. 2008a,b, Furlow et al. Figure 3 Functional imaging with [68Ga]-DOTATATE, [18F]-FDG, [18F]-FDOPA and [18F]-FDA PET/CT in patient No. 2.”
Erythropoietin in Brain Development and Beyond
Alnaeeli, M., Wang, L., Piknova, B., Rogers, H. M., Li, X., & Noguchi, C. T. (2012) · Anatomy Research International · doi:10.1155/2012/953264 · Cited by 63 · see citing works
“The corresponding receptors for the hematopoietic class 1 cytokines are single transmembrane polypeptides that associate as homodimers, as is the case with EpoR, heterodimers, or heterotrimers.”
BackgroundSelf-citationRenal anemia: from incurable to curable
Sato, Y., & Yanagita, M. (2013) · American Journal of Physiology-Renal Physiology · doi:10.1152/ajprenal.00233.2013 · Cited by 65 · see citing works
“A gain-of-function mutation in the HIF-2 gene has been also reported to be responsible for excessive erythrocytosis in humans (100).”
BackgroundTaïeb, D., Yang, C., Delenne, B., Zhuang, Z., Barlier, A., Sebag, F. A., & Pacák, K. (2013) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2013-1217 · Cited by 56 · see citing works
“To date, the genes of the oxygen-sensing pathway in which polycythemia-associated mutations have been identified include VHL (von Hippel-Lindau; Chuvash polycythemia) (1), PHD2 (prolyl hydroxylase domain 2 containing protein) (2), and HIF2A (hypoxia-inducible factor 2 ) (3).”
BackgroundZheng, Q., Yang, H., Sun, L., Wei, R., Fu, X., Wang, Y., Huang, Y., Liu, Y., & Liu, W. J. (2020) · Pharmacological Research · doi:10.1016/j.phrs.2020.105020 · Cited by 76 · see citing works
Pietras, A., Johnsson, A. S., & Påhlman, S. (2010) · Current topics in microbiology and immunology · doi:10.1007/82_2010_72 · Cited by 58 · see citing works
Hypoxia. 5. Hypoxia and hematopoiesis
Yoon, D., Ponka, P., & Prchal, J. T. (2011) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00044.2011 · Cited by 61 · see citing works
“A family was described in which members with polycythemia were heterozygous carriers of a HIF-2 Gly537Trp mutation that served to stabilize the HIF-2 protein (3, 54).”
BackgroundSelection signatures for high‐altitude adaptation in ruminants
Friedrich, J., & Wiener, P. (2020) · Animal Genetics · doi:10.1111/age.12900 · Cited by 65 · see citing works
Genetics of pheochromocytoma and paraganglioma syndromes
Vícha, A., Musil, Z., & Pacák, K. (2013) · Current Opinion in Endocrinology Diabetes and Obesity · doi:10.1097/med.0b013e32835fcc45 · Cited by 54 · see citing works
“Dominantly inherited gain-offunction mutations of HIF2A were previously found to be associated with an increase of erythropoietin and congenital polycythemia [30,31].”
BackgroundFurlow, P. W., Percy, M. J., Sutherland, S., Bierl, C., McMullin, M. F., Master, S. R., Lappin, T. R. J., & Lee, F. S. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.m808737200 · Cited by 58 · see citing works
Inherited predisposition to myeloproliferative neoplasms
Jones, A. V., & Cross, N. C. P. (2013) · Therapeutic Advances in Hematology · doi:10.1177/2040620713489144 · Cited by 53 · see citing works
- Authors
- Percy, M. J., Furlow, P. W., Lucas, G. S., Li, X., Lappin, T. R. J., McMullin, M. F., & Lee, F. S.
- Affiliations
- Belfast City Hospital (GB)
- University of Pennsylvania (US)
- Manchester Royal Infirmary (GB)
- Queen's University (CA)
- Venue
- New England Journal of Medicine
- Publisher
- Massachusetts Medical Society
- Published
- 2008-01-10
- Volume
- 358
- Issue
- 2
- Pages
- 162-168
- ISSN
- 0028-4793 (ISSN-L)
- 1533-4406
- PMC
- PMC2295209
- OpenAlex
- W2086913408
- Cited by
- 314
- References
- 0
- Citations by year
- 2026: 6 · 2025: 3 · 2024: 8 · 2023: 14 · 2022: 8 · 2021: 16 · 2020: 24 · 2019: 23 · 2018: 16 · 2017: 14 · 2016: 14 · 2015: 13 · 2014: 22 · 2013: 25 · 2012: 19
- FWCI
- 19.37
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- New England Journal of Medicine (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Research Portal (Queen's University Belfast) (submittedVersion)
- Funders
- University of Pennsylvania
- U.S. Public Health Service (R01 C090261)
- 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 › Hemoglobinopathies and Related Disorders
- Keywords
- HIF-2α, familial erythrocytosis, gain-of-function mutations, hypoxia-inducible factor alpha, protein stabilization, erythropoietin regulation, erythropoiesis, hereditary erythrocytosis
- MeSH terms
- Endothelial PAS Domain-Containing Protein 1, Adult, DNA Mutational Analysis, Erythropoiesis, Erythropoietin, Female, Genotype, Hematocrit, Hemoglobins, Humans, Male, Pedigree, Polycythemia, Polymerase Chain Reaction, Point Mutation, Basic Helix-Loop-Helix Transcription Factors, Basic Helix-Loop-Helix Proteins
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