A novel EPAS1/HIF2A germline mutation in a congenital polycythemia with paraganglioma
Open accessAbstract
Congenital polycythemias have diverse etiologies, including mutations in the hypoxia sensing pathway. These include HIF2A at exon 12, VHL gene (Chuvash polycythemia), and PHD2 mutations, which in one family was also associated with recurrent pheochromocytoma/paraganglioma (PHEO/PGL). Over the past two decades, we have studied seven unrelated patients with sporadic congenital polycythemia who subsequently developed PHEO/PGL with, until now, no discernible molecular basis. We now report a polycythemic patient with a novel germline HIF2A (F374Y) (exon 9) mutation, inherited from his mother, who developed PHEO/PGL. We show that this is a gain-of-function mutation and demonstrate no loss-of-heterozygosity or additional somatic mutation of HIF2A in the tumor, indicating HIF2A (F374Y) may be predisposing rather than causative of PHEO/PGL. This report, in view of two other concomitantly reported PHEO/PGL patients with somatic mutations of HIF2A and polycythemia, underscores the PHEO/PGL-promoting potential of mutations of HIF2A that alone are not sufficient for PHEO/PGL development.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Somatic gain-of-function mutations in HIF2A have been discovered in pheochromocytomas and paragangliomas.
“Somatic gain-of-function mutations in HIF2A have been discovered in pheochromocytomas and paragangliomas (Zhuang et al., 2012;Comino-Mendez et al., 2013;Lorenzo et al., 2013;Taieb et al., 2013;Toledo et al., 2013;Yang et al., 2013), while high HIF-2α expression is associated with poor survival in patients with neuroblastoma (Holmquist-Mengelbier et al., 2006).”
From Therapeutic targeting of hypoxia and hypoxia-inducible factors in cancer (2016) · cites this paper as Lorenzo et al., 2013
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 [153]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
The citation lists haven’t been fetched yet
References 24 · Cited by 171
Research works printed but not linked: 18
- [1]Prchal JT Classification and molecular biology of polycythemias (erythrocytoses) and thrombocytosis. Hematol Oncol Clin North Am 2003 17 1151 1158 vi 14560779
- [2]Semenza GL HIF-1 and mechanisms of hypoxia sensing. Curr Opin Cell Biol 2001 13 167 171 11248550
- [3]Wang GL Semenza GL General involvement of hypoxia-inducible factor 1 in transcriptional response to hypoxia. Proc Natl Acad Sci USA 1993 90 4304 4308 8387214 PMC46495
- [6]Ang SO Chen H Hirota K Gordeuk VR Jelinek J Guan Y Liu E Sergueeva AI Miasnikova GY Mole D Disruption of oxygen homeostasis underlies congenital Chuvash polycythemia. Nat Genet 2002 32 614 621 12415268
- [7]Pastore Y Jedlickova K Guan Y Liu E Fahner J Hasle H Prchal JF Prchal JT Mutations of von Hippel-Lindau tumor-suppressor gene and congenital polycythemia. Am J Hum Genet 2003 73 412 419 12844285 PMC1180379
- [8]Percy MJ Furlow PW Beer PA Lappin TR McMullin MF Lee FS A novel erythrocytosis-associated PHD2 mutation suggests the location of a HIF binding groove. Blood 2007 110 2193 2196 17579185 PMC1976349
- [10]Tian H McKnight SL Russell DW Endothelial PAS domain protein 1 (EPAS1), a transcription factor selectively expressed in endothelial cells. Genes Dev 1997 11 72 82 9000051
- [11]Semenza GL Regulation of oxygen homeostasis by hypoxia-inducible factor 1. Physiology (Bethesda) 2009 24 97 106 19364912
- [12]Gruber M Hu CJ Johnson RS Brown EJ Keith B Simon MC Acute postnatal ablation of Hif-2alpha results in anemia. Proc Natl Acad Sci U S A 2007 104 2301 2306 17284606 PMC1892942
- [13]Yoon D Pastore YD Divoky V Liu E Mlodnicka AE Rainey K Ponka P Semenza GL Schumacher A Prchal JT Hypoxia-inducible factor-1 deficiency results in dysregulated erythropoiesis signaling and iron homeostasis in mouse development. J Biol Chem 2006 281 25703 25711 16787915
- [14]Yoon D Ponka P Prchal JT Hypoxia. 5. Hypoxia and hematopoiesis. Am J Physiol Cell Physiol 2011 300 C1215 1222 21368293
- [15]Semenza GL Hypoxia-inducible factors in physiology and medicine. Cell 2012 148 399 408 22304911 PMC3437543
- [16]Semenza GL HIF-1 mediates the Warburg effect in clear cell renal carcinoma. J Bioenerg Biomembr 2007 39 231 234 DOI 10.1007/s10863-007-9081-2 17551816 · DOI
- [18]Friedrich CA Genotype-phenotype correlation in von Hippel-Lindau syndrome. Hum Mol Genet 2001 10 763 767 11257110
- [19]Richards FM Webster AR McMahon R Woodward ER Rose S Maher ER Molecular genetic analysis of von Hippel-Lindau disease. J Intern Med 1998 243 527 533 9681854
- [20]Koivunen P Lee S Duncan CG Lopez G Lu G Ramkissoon S Losman JA Joensuu P Bergmann U Gross S Transformation by the (R)-enantiomer of 2-hydroxyglutarate linked to EGLN activation. Nature 2012 483 484 488 22343896 PMC3656605
- [21]Erbel PJ Card PB Karakuzu O Bruick RK Gardner KH Structural basis for PAS domain heterodimerization in the basic helix--loop--helix-PAS transcription factor hypoxia-inducible factor. Proc Natl Acad Sci U S A 2003 100 15504 15509 14668441 PMC307597
- [24]Kralovics R Sokol L Prchal JT Absence of polycythemia in a child with a unique erythropoietin receptor mutation in a family with autosomal dominant primary polycythemia. J Clin Invest 1998 102 124 129 9649565 PMC509073
- Authors
- Lorenzo, F. R., Yang, C., Ng Tang Fui, M., Vankayalapati, H., Zhuang, Z., Huynh, T., Grossmann, M., Pacak, K., & Prchal, J. T.
- Affiliations
- University of Utah (US)
- National Institutes of Health (US)
- The University of Melbourne (AU)
- Corresponding author
- Prchal, Josef T.
- ORCID
- Venue
- Journal of Molecular Medicine
- Published
- 2012-10-23
- Volume
- 91
- Issue
- 4
- Pages
- 507-512
- ISSN
- 0946-2716 (ISSN-L)
- 1432-1440
- PMC
- PMC3570726
- OpenAlex
- W2032428330
- Cited by
- 171
- References
- 24
- Citations by year
- 2026: 2 · 2025: 3 · 2024: 5 · 2023: 6 · 2022: 10 · 2021: 17 · 2020: 6 · 2019: 10 · 2018: 16 · 2017: 22 · 2016: 17 · 2015: 10 · 2014: 26 · 2013: 21
- FWCI
- 18.61
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Journal of Molecular Medicine (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health
- National Heart, Lung, and Blood Institute (R01HL050077)
- National Cancer Institute (P01CA108671)
- Topics
- Health Sciences › Medicine › Surgery › Adrenal and Paraganglionic Tumors
- Health Sciences › Medicine › Oncology › Ear and Head Tumors
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Keywords
- EPAS1, HIF-2α, germline mutations, paraganglioma, pheochromocytoma, gain-of-function mutations, hereditary cancer predisposition, loss of heterozygosity
- MeSH terms
- Endothelial PAS Domain-Containing Protein 1, Aged, 80 and over, Amino Acid Sequence, Base Sequence, Female, Humans, Male, Middle Aged, Models, Molecular, Molecular Sequence Data, Paraganglioma, Polycythemia, Protein Conformation, Sequence Alignment, Germ-Line Mutation, Basic Helix-Loop-Helix Transcription Factors, Basic Helix-Loop-Helix Proteins
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
