The DOI matches its Crossref record; 9 of the 9 references it cites were found in a registry or an index.
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.
Overview
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
Verification
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?
In the citing paper
“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]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
Targeting HIF-1 for cancer therapy
Semenza, G. L. (2003) · Nature Reviews Cancer · doi:10.1038/nrc1187 · Cited by 6,717
Oxygen sensing by HIF hydroxylases
Schofield, C. J., & Ratcliffe, P. J. (2004) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm1366 · Cited by 2,068
Characterization of the human prolyl 4-hydroxylases that modify the hypoxia-inducible factor
Hirsilä, M., Koivunen, P., Günzler, V., Kivirikko, K. I., & Myllyharju, J. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m304982200 · Cited by 794
Hypoxia-inducible factor-2 (HIF-2) regulates hepatic erythropoietin in vivo
Rankin, E. B., Biju, M. P., Liu, Q., Unger, T. L., Rha, J., Johnson, R. S., Simon, M. C., Keith, B., & Haase, V. H. (2007) · Journal of Clinical Investigation · doi:10.1172/jci30117 · Cited by 596
Disruption of oxygen homeostasis underlies congenital Chuvash polycythemia
Ang, S. O., Chen, H., Hirota, K., Gordeuk, V. R., Jelinek, J., Guan, Y., Liu, E., Sergueeva, A. I., Miasnikova, G. Y., Mole, D., et al. (2002) · Nature Genetics · doi:10.1038/ng1019 · Cited by 510
Proline hydroxylation and gene expression
Kaelin, W. G. (2005) · Annual Review of Biochemistry · doi:10.1146/annurev.biochem.74.082803.133142 · Cited by 468
Percy, M. J., Zhao, Q., Flores, A., Harrison, C., Lappin, T. R. J., Maxwell, P. H., McMullin, M. F., & Lee, F. S. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0508423103 · Cited by 330
Self-citationHuang, J., Zhao, Q., Mooney, S. M., & Lee, F. S. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m206955200 · Cited by 307
Self-citationFailure to prolyl hydroxylate hypoxia‐inducible factor α phenocopies VHL inactivation in vivo
Kim, W. Y., Safran, M., Buckley, M. R., Ebert, B. L., Glickman, J., Bosenberg, M., Regan, M., & Kaelin, W. G. (2006) · The EMBO Journal · doi:10.1038/sj.emboj.7601300 · Cited by 235
Flagged first, then by citations
Research works printed but not linked: 16
- 10.1182/blood-2006-08-019083 · DOI
- 10.1016/j.gde.2006.12.006 · DOI
- 10.4161/cc.5.9.2723 · DOI
- 10.1182/blood-2007-04-084434 · DOI · Paper page
- 10.1182/blood-2002-10-3246 · DOI · Paper page
- 10.1172/JCI5912 · DOI
- 10.1038/nm723 · DOI
- 10.1074/jbc.M602329200 · DOI
- 10.1182/blood-2003-02-0448 · DOI
- 10.1073/pnas.0608382104 · DOI · Paper page
- 10.1111/j.1365-2141.2005.05535.x · DOI
- 10.1046/j.1365-2141.1998.00550.x · DOI
- 10.1182/blood-2002-06-1843 · DOI · Paper page
- 10.1093/nar/29.17.e88 · DOI
- 10.1042/BJ20060635 · DOI
- 10.1128/MCB.25.8.3163-3172.2005 · DOI
Cited by
Sorted by citations
Eltzschig, H. K., & Carmeliet, P. (2011) · New England Journal of Medicine · doi:10.1056/nejmra0910283 · Cited by 2,061
Sequencing of 50 Human Exomes Reveals Adaptation to High Altitude
Yi, X., Liang, Y., Huerta-Sanchez, E., Jin, X., Cuo, Z. X. P., Pool, J. E., Xu, X., Jiang, H., Vinckenbosch, N., Korneliussen, T. S., et al. (2010) · Science · doi:10.1126/science.1190371 · Cited by 1,611
The impact of O2 availability on human cancer
Bertout, J. A., Patel, S. A., & Simon, M. C. (2008) · Nature Reviews Cancer · doi:10.1038/nrc2540 · Cited by 1,365
Oxygen Sensing, Homeostasis, and Disease
Semenza, G. L. (2011) · New England Journal of Medicine · doi:10.1056/nejmra1011165 · Cited by 1,014
Beall, C. M., Cavalleri, G. L., Deng, L., Elston, R. C., Gao, Y., Knight, J., Li, C., Li, J. C., Liang, Y., McCormack, M., et al. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1002443107 · Cited by 845
Regulation of erythropoiesis by hypoxia-inducible factors
Haase, V. H. (2013) · Blood Reviews · doi:10.1016/j.blre.2012.12.003 · Cited by 787
High-resolution genome-wide mapping of HIF-binding sites by ChIP-seq
Schödel, J., Oikonomopoulos, S., Ragoussis, J., Pugh, C. W., Ratcliffe, P. J., & Mole, D. R. (2011) · Blood · doi:10.1182/blood-2010-10-314427 · Cited by 724
Wound healing essentials: Let there be oxygen
Sen, C. K. (2009) · Wound Repair and Regeneration · doi:10.1111/j.1524-475x.2008.00436.x · Cited by 738
“HIF-2a regulates erythropoietin production in adults.(179) HIF-1a functions as an upstream player in the p21-mediated growth arrest of keratinocytes.”
BackgroundPrabhakar, N. R., & Semenza, G. L. (2012) · Physiological Reviews · doi:10.1152/physrev.00030.2011 · Cited by 641
“HIF-2 appears to play a particularly important role in the regulation of EPO gene expression and erythropoiesis as evidenced by loss-of-function mutation in mice (104) and gain-of-function mutation in humans (259).”
BackgroundPheochromocytoma and paraganglioma pathogenesis: learning from genetic heterogeneity
Dahia, P. L. M. (2014) · Nature Reviews Cancer · doi:10.1038/nrc3648 · Cited by 545
The stimulation of thrombosis by hypoxia
Gupta, N., Zhao, Y., & Evans, C. E. (2019) · Thrombosis Research · doi:10.1016/j.thromres.2019.07.013 · Cited by 455
Somatic HIF2A Gain-of-Function Mutations in Paraganglioma with Polycythemia
Zhuang, Z., Yang, C., Lorenzo, F., Merino, M., Fojo, T., Kebebew, E., Popovic, V., Stratakis, C. A., Prchal, J. T., & Pacak, K. (2012) · New England Journal of Medicine · doi:10.1056/nejmoa1205119 · Cited by 397
The IRP/IRE system in vivo: insights from mouse models
Wilkinson, N., & Pantopoulos, K. (2014) · Frontiers in Pharmacology · doi:10.3389/fphar.2014.00176 · Cited by 366
“…which are also manifested in patients with Chuvash polycythemia (Ang et al., 2002), and other forms of familial polycythemia caused by “gain of function” HIF2α mutations (Percy et al., 2008), or inactivating mutations in pVHL, a negative regulator of HIF2α stability (Percy et al., 2006).”
BackgroundTargeting hypoxia signalling for the treatment of ischaemic and inflammatory diseases
Eltzschig, H. K., Bratton, D. L., & Colgan, S. P. (2014) · Nature Reviews Drug Discovery · doi:10.1038/nrd4422 · Cited by 364
Generating specificity and diversity in the transcriptional response to hypoxia
Lendahl, U., Lee, K. L., Yang, H. H., & Poellinger, L. (2009) · Nature Reviews Genetics · doi:10.1038/nrg2665 · Cited by 333
Hypoxic regulation of erythropoiesis and iron metabolism
Haase, V. H. (2010) · American Journal of Physiology-Renal Physiology · doi:10.1152/ajprenal.00174.2010 · Cited by 347
Human high-altitude adaptation: forward genetics meets the HIF pathwayPreprint
Bigham, A. W., & Lee, F. S. (2014) · Genes & Development · doi:10.1101/gad.250167.114 · Cited by 364
“In humans, important evidence for a role of HIF-2a in EPO regulation is provided by the identification of heterozygous GOF mutations in the HIF2A gene in patients with erythrocytosis (Percy et al. 2008a,b).”
BackgroundSelf-citationInhibition of oxygen sensors as a therapeutic strategy for ischaemic and inflammatory disease
Fraisl, P., Aragonés, J., & Carmeliet, P. (2009) · Nature Reviews Drug Discovery · doi:10.1038/nrd2761 · Cited by 326
PHD2 Mutation and Congenital Erythrocytosis with Paraganglioma
Ladroue, C., Carcenac, R., Leporrier, M., Gad, S., Le Hello, C., Galateau-Salle, F., Feunteun, J., Pouysségur, J., Richard, S., & Gardie, B. (2008) · New England Journal of Medicine · doi:10.1056/nejmoa0806277 · Cited by 323
Anaemia in kidney disease: harnessing hypoxia responses for therapy
Koury, M. J., & Haase, V. H. (2015) · Nature Reviews Nephrology · doi:10.1038/nrneph.2015.82 · Cited by 313
Pharmacologic Targeting of Hypoxia-Inducible Factors
Semenza, G. L. (2019) · Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev-pharmtox-010818-021637 · Cited by 288
HIF prolyl hydroxylase inhibitors for the treatment of renal anaemia and beyond
Maxwell, P. H., & Eckardt, K. (2015) · Nature Reviews Nephrology · doi:10.1038/nrneph.2015.193 · Cited by 288
Chen, R., Lai, U. H., Zhu, L., Singh, A., AlKataan, M. A. A., & Forsyth, N. R. (2018) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2018.00132 · Cited by 285
“Carbonic anhydrase 9 and BNIP3 are HIF1 downstream genes, while HIF2 is the main driver of EPO production (Ratcliffe, 2007; Percy et al., 2008).”
Targeting hypoxia-inducible factors: therapeutic opportunities and challenges
Yuan, X., Ruan, W., Bobrow, B., Carmeliet, P., & Eltzschig, H. K. (2024) · Nature Reviews Drug Discovery · doi:10.1038/s41573-023-00848-6 · Cited by 245
Involvement of oxygen-sensing pathways in physiologic and pathologic erythropoiesis
Semenza, G. L. (2009) · Blood · doi:10.1182/blood-2009-05-189985 · Cited by 228
Erythropoiesis: Model systems, molecular regulators, and developmental programs
Tsiftsoglou, A. S., Vizirianakis, I. S., & Strouboulis, J. (2009) · IUBMB Life · doi:10.1002/iub.226 · Cited by 217
Gou, X., Wang, Z., Li, N., Qiu, F., Xu, Z., Yan, D., Yang, S., Jia, J., Kong, X., Wei, Z., et al. (2014) · Genome Research · doi:10.1101/gr.171876.113 · Cited by 216
“On one hand, clin- ical case studies found that several gain-of-function mutations occurred in close vicinity to the primary hydroxylation site (Pro531) at EPAS1 cause erythrocytosis (Percy et al. 2008a,b).”
BackgroundHypoxia-inducible factors link iron homeostasis and erythropoiesis
Shah, Y. M., & Xie, L. (2014) · Gastroenterology · doi:10.1053/j.gastro.2013.12.031 · Cited by 187
The HIF pathway and erythrocytosis
Lee, F. S., & Percy, M. J. (2011) · Annual Review of Pathology Mechanisms of Disease · doi:10.1146/annurev-pathol-011110-130321 · Cited by 177
Self-citationPaliege, A., Rosenberger, C., Bondke, A., Sciesielski, L. K., Shina, A., Heyman, S. N., Flippin, L. A., Arend, M., Klaus, S. J., & Bachmann, S. (2009) · Kidney International · doi:10.1038/ki.2009.460 · Cited by 171
The Many Facets of Erythropoietin Physiologic and Metabolic Response
Suresh, S., Rajvanshi, P. K., & Noguchi, C. T. (2020) · Frontiers in Physiology · doi:10.3389/fphys.2019.01534 · Cited by 217
An overview of 20 years of genetic studies in pheochromocytoma and paraganglioma
Buffet, A., Burnichon, N., Favier, J., & Gimenez‐Roqueplo, A. (2020) · Best Practice & Research Clinical Endocrinology & Metabolism · doi:10.1016/j.beem.2020.101416 · Cited by 202
A novel EPAS1/HIF2A germline mutation in a congenital polycythemia with paraganglioma
Lorenzo, F. R., Yang, C., Ng Tang Fui, M., Vankayalapati, H., Zhuang, Z., Huynh, T., Grossmann, M., Pacak, K., & Prchal, J. T. (2013) · Journal of Molecular Medicine · doi:10.1007/s00109-012-0967-z · Cited by 171
“In many instances, such as VHL syndrome, upregulated HIFs are tumor promoter genes, but in some contexts, HIFs can also have a role as tumor suppressors [20].”
InfluentialKaluz, Š., Kaluzová, M., & Stanbridge, E. J. (2008) · Clinica Chimica Acta · doi:10.1016/j.cca.2008.05.002 · Cited by 179
“This notion is further supported by a linkage of familial erythrocytosis with a gain-of-function mutation in HIF-2α [101].”
BackgroundGale, D. P., Harten, S. K., Reid, C. D. L., Tuddenham, E. G. D., & Maxwell, P. H. (2008) · Blood · doi:10.1182/blood-2008-04-153718 · Cited by 157
Comino-Méndez, I., de Cubas, A. A., Bernal, C., Álvarez-Escolá, C., Sánchez-Malo, C., Ramírez-Tortosa, C. L., Pedrinaci, S., Rapizzi, E., Ercolino, T., Bernini, G., et al. (2013) · Human Molecular Genetics · doi:10.1093/hmg/ddt069 · Cited by 169
New Syndrome of Paraganglioma and Somatostatinoma Associated With Polycythemia
Pacák, K., Jochmanová, I., Prodanov, T., Yang, C., Merino, M. J., Fojo, T., Prchal, J. T., Tischler, A. S., Lechan, R. M., & Zhuang, Z. (2013) · Journal of Clinical Oncology · doi:10.1200/jco.2012.47.1912 · Cited by 157
Sims, A. M., Tilton, S. C., Menachery, V. D., Gralinski, L. E., Schäfer, A., Matzke, M. M., Webb‐Robertson, B., Chang, J., Luna, M. L., Long, C., et al. (2013) · Journal of Virology · doi:10.1128/jvi.02520-12 · Cited by 156
“The transcription factor EpasI/HIF 2 is critical for responding to reduced oxygen levels in the intracellular environment (75).”
BackgroundTargeting Hypoxia-Inducible Factors for the Treatment of Anemia in Chronic Kidney Disease Patients
Locatelli, F., Fishbane, S. N., Block, G. A., & Macdougall, I. C. (2017) · American Journal of Nephrology · doi:10.1159/000455166 · Cited by 4,836
IRP1 regulates erythropoiesis and systemic iron homeostasis by controlling HIF2α mRNA translation
Wilkinson, N., & Pantopoulos, K. (2013) · Blood · doi:10.1182/blood-2013-03-492454 · Cited by 136
“These include Chuvash polycythemia, which is caused by pVHL mutations,(21-23) and familial erythrocytosis with paraganglioma caused by inactivating mutations in PHD2(24-26) or gain-of-function HIF2a mutations that prevent its interaction with pVHL.(27) Similar phenotypes are also observed in mice where HIF2a is stabil…”
BackgroundGenetic Basis of Congenital Erythrocytosis: Mutation Update and Online Databases
Bento, C., Percy, M. J., Gardie, B., Maia, T. M., van Wijk, R., Perrotta, S., Ragione, F. D., Almeida, H., Rossi, C., Girodon, F., et al. (2013) · Human Mutation · doi:10.1002/humu.22448 · Cited by 131
Self-citationPetousi, N., Croft, Q. P. P., Cavalleri, G. L., Cheng, H., Formenti, F., Ishida, K., Lunn, D., McCormack, M., Shianna, K. V., Talbot, N. P., et al. (2013) · Journal of Applied Physiology · doi:10.1152/japplphysiol.00535.2013 · Cited by 139
“dividuals are homozygous for a hypomorphic allele of the von Hippel-Lindau (VHL) tumor suppressor, which impairs HIF degradation (2), and HIF2 gain-of-function mutations (30, 31).”
BackgroundHypoxia. 1. Intracellular sensors for oxygen and oxidative stress: novel therapeutic targets
Miyata, T., Takizawa, S., & de Strihou, C. V. Y. (2010) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00430.2010 · Cited by 131
Novel exon 12 mutations in the HIF2A gene associated with erythrocytosis
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., et al. (2008) · Blood · doi:10.1182/blood-2008-02-137703 · Cited by 127
Self-citationHypoxia and Mucosal Inflammation
Colgan, S. P., Campbell, E. L., & Kominsky, D. J. (2016) · Annual Review of Pathology Mechanisms of Disease · doi:10.1146/annurev-pathol-012615-044231 · Cited by 137
Hypoxia-Regulated Delta-like 1 Homologue Enhances Cancer Cell Stemness and Tumorigenicity
Kim, Y., Lin, Q., Zelterman, D. A., & Yun, Z. (2009) · Cancer Research · doi:10.1158/0008-5472.can-09-1605 · Cited by 123
Sugahara, M., Tanaka, T., & Nangaku, M. (2017) · Kidney International · doi:10.1016/j.kint.2017.02.035 · Cited by 151
The classification and diagnosis of erythrocytosis
McMullin, M. F. (2008) · International Journal of Laboratory Hematology · doi:10.1111/j.1751-553x.2008.01102.x · Cited by 115
“In vitro studies showed that this mutation would result in major change in function of the protein (Percy et al., 2008).”
BackgroundSelf-citationHypoxia: Adapting to High Altitude by Mutating EPAS-1 , the Gene Encoding HIF-2α
Tissot van Patot, M. C., & Gassmann, M. (2011) · High Altitude Medicine & Biology · doi:10.1089/ham.2010.1099 · Cited by 119
“…of recent data demonstrating genetic variation in EPAS-1 resulting in phenotypic differences (Yi et al. 2010; Beall et al. 2010; Bigham et al. 2009; Percy et al. 2008), it is possible that the gene encoding HIF-1 a gene was replicated at some point in evolution giving rise to EPAS-1 and HIF-2 a .”
InfluentialPetousi, N., & Robbins, P. A. (2013) · Journal of Applied Physiology · doi:10.1152/japplphysiol.00605.2013 · Cited by 127
The Genomics and Genetics of Oxygen Homeostasis
Semenza, G. L. (2020) · Annual Review of Genomics and Human Genetics · doi:10.1146/annurev-genom-111119-073356 · Cited by 139
The complete evaluation of erythrocytosis: congenital and acquired
Patnaik, M. M., & Tefferi, A. (2009) · Leukemia · doi:10.1038/leu.2009.54 · Cited by 125
Erythrocytosis: the HIF pathway in control
Franke, K., Gassmann, M., & Wielockx, B. (2013) · Blood · doi:10.1182/blood-2013-01-478065 · Cited by 116
“The mutation is predicted to produce a G537W change in the amino acid sequence of HIF2a, which is very close to the primary site of hydroxylation (Pro-531).(69) The resulting impairment of the hydroxylation of HIF2a and its subsequent VHL binding leads to an aberrant stabilization of this transcription factor during n…”
BackgroundResultProlyl Hydroxylase Domain Inhibitors: A Route to HIF Activation and Neuroprotection
Harten, S. K., Ashcroft, M. A., & Maxwell, P. H. (2009) · Antioxidants and Redox Signaling · doi:10.1089/ars.2009.2870 · Cited by 99
“Genetic defects have been identi-fied in VHL (hypomorphic allele), PHD2 (haploinsufficiency), and HIF-2 a (activating mutation), which are associated with excess EPO production in patients (9, 63, 135, 189, 190).”
Semenza, G. L. (2009) · WIREs Systems Biology and Medicine · doi:10.1002/wsbm.69 · Cited by 324
Regulated oxygen sensing by protein hydroxylation in renal erythropoietin-producing cells
Wenger, R. H., & Hoogewijs, D. (2010) · American Journal of Physiology-Renal Physiology · doi:10.1152/ajprenal.00736.2009 · Cited by 120
“The mouse data have recently been confirmed by the identification of HIF-2 P534L, M535V, M535I, G537W, G537R, and D539E mutations that cause human familial erythrocytosis (36, 37, 80, 102, 104, 107, 138).”
BackgroundSurvival and proliferative roles of erythropoietin beyond the erythroid lineage
Noguchi, C. T., Wang, L., Rogers, H. M., Teng, R., & Jia, Y. (2008) · Expert Reviews in Molecular Medicine · doi:10.1017/s1462399408000860 · Cited by 113
Physiology and pathophysiology of renal erythropoietin-producing cells
Shih, H., Wu, C., & Lin, S. (2018) · Journal of the Formosan Medical Association · doi:10.1016/j.jfma.2018.03.017 · Cited by 140
Erythrocytosis and Pulmonary Hypertension in a Mouse Model of Human HIF2A Gain of Function Mutation
Tan, Q., Kerestes, H., Percy, M. J., Pietrofesa, R. A., Chen, L., Khurana, T. S., Christofidou‐Solomidou, M., Lappin, T. R. J., & Lee, F. S. (2013) · Journal of Biological Chemistry · doi:10.1074/jbc.m112.444059 · Cited by 104
“We recently identified a heterozygous gain of function missense mutation in the HIF2A gene associated with erythrocytosis (19).”
BackgroundSelf-citationHIF-α Prolyl Hydroxylase Inhibitors and Their Implications for Biomedicine: A Comprehensive Review
Hirota, K. (2021) · Biomedicines · doi:10.3390/biomedicines9050468 · Cited by 115
Song, S., Yao, N., Yang, M., Liu, X., Dong, K., Zhao, Q., Pu, Y., He, X., Guan, W., Yang, N., et al. (2016) · BMC Genomics · doi:10.1186/s12864-016-2449-0 · Cited by 114
Yang, C., Sun, M. G., Matro, J. C., Huynh, T., Rahimpour, S., Prchal, J. T., Lechan, R. M., Lonser, R. R., Pacák, K., & Zhuang, Z. (2013) · Blood · doi:10.1182/blood-2012-10-460972 · Cited by 95
“Genetic changes in key elements of hypoxia-sensing pathways, such as germline mutations in VHL or EGLN1, are essential for the establishment of polycythemia.(7,8) Percy et al(9) reported novel HIF2A mutations (M535V, G537R) associated with polycythemia as a result of constitutively activated hypoxic cell signaling.”
BackgroundHypoxia and Hypoxia-Inducible Factor in Renal Disease
Nangaku, M., Inagi, R., Miyata, T., & Fujita, T. (2008) · Nephron Experimental Nephrology · doi:10.1159/000148256 · Cited by 92
Mosaicism inHIF2A-Related Polycythemia-Paraganglioma Syndrome
Buffet, A., Smati, S., Mansuy, L., Menara, M., Bras, M. L., Heymann, M., Simian, C., Favier, J., Murat, A., Cariou, B., et al. (2013) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2013-2600 · Cited by 105
Clinical iron deficiency disturbs normal human responses to hypoxia
Frise, M. C., Cheng, H., Nickol, A. H., Curtis, M. K., Pollard, K. A., Roberts, D. J., Ratcliffe, P. J., Dorrington, K. L., & Robbins, P. A. (2016) · Journal of Clinical Investigation · doi:10.1172/jci85715 · Cited by 105
“Spontaneously occurring mutations in humans confirm this to be the case, with genetic upregulation of the pathway resulting in polycythaemia, pulmonary arterial hypertension, abnormal ventilatory drive and impaired skeletal muscle oxidative phosphorylation (14-18).”
Formenti, F., Beer, P. A., Croft, Q. P. P., Dorrington, K. L., Gale, D. P., Lappin, T. R. J., Lucas, G. S., Maher, E. R., Maxwell, P. H., McMullin, M. F., et al. (2011) · The FASEB Journal · doi:10.1096/fj.10-177378 · Cited by 92
“They were identified from previous studies (25, 28) and recruited through their respective physicians.”
BackgroundMethodSelf-citationHypoxia-Inducible Factor and Its Role in the Management of Anemia in Chronic Kidney Disease
Kaplan, J., Sharma, N., & Dikdan, S. J. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19020389 · Cited by 108
Camps, C., Petousi, N., Bento, C., Cario, H., Copley, R. R., McMullin, M. F., van Wijk, R., Ratcliffe, P. J., Robbins, P. A., & Taylor, J. C. (2016) · Haematologica · doi:10.3324/haematol.2016.144063 · Cited by 93
“G537R – a well-described gain-of-function mutation found in erythrocytosis patients (30, 31) – was detected.”
BackgroundSelf-citationTherapeutic Manipulation of the HIF Hydroxylases
Nagel, S., Talbot, N. P., Mecinović, J., Smith, T. G., Buchan, A. M., & Schofield, C. J. (2009) · Antioxidants and Redox Signaling · doi:10.1089/ars.2009.2711 · Cited by 77
“Intravenous administration of DFO increases EPO production in healthy volunteers (11, 158, 183) and excessive erythropoiesis has been reported in families with HIFactivating mutations (3, 61, 108, 149, 150).”
Increased prevalence of EPAS1 variant in cattle with high-altitude pulmonary hypertension
Newman, J. H., Holt, T. N., Cogan, J. D., Womack, B., Phillips, J. A., Li, C., Kendall, Z., Stenmark, K. R., Thomas, M., Brown, R. D., et al. (2015) · Nature Communications · doi:10.1038/ncomms7863 · Cited by 84
Genetic Variants in EPAS1 Contribute to Adaptation to High-Altitude Hypoxia in Sherpas
Hanaoka, M., Droma, Y., Basnyat, B., Ito, M., Kobayashi, N., Katsuyama, Y., Kubo, K., & Ôta, M. (2012) · PLoS ONE · doi:10.1371/journal.pone.0050566 · Cited by 95
Yan, L. Y., Colandrea, V. J., & Hale, J. J. (2010) · Expert Opinion on Therapeutic Patents · doi:10.1517/13543776.2010.510836 · Cited by 87
“Several patients with familial erythrocytosis were found to carry mutations in HIF2A gene [26-28].”
BackgroundDavis, L., Recktenwald, M., Hutt, E., Fuller, S., Briggs, M., Goel, A., & Daringer, N. (2022) · Cancers · doi:10.3390/cancers14051259 · Cited by 83
Hypoxia Pathway Proteins are Master Regulators of Erythropoiesis
Watts, D., Gaete, D., Rodriguez, D., Hoogewijs, D., Rauner, M., Sormendi, S., & Wielockx, B. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21218131 · Cited by 90
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
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 81
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 86
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 86
“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 79
Investigation and Management of Erythrocytosis
McMullin, M. F. (2016) · Current Hematologic Malignancy Reports · doi:10.1007/s11899-016-0334-1 · Cited by 49
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 82
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
“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
“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
“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
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 85
“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 87
Hypoxic regulation of mRNA expression
Gardner, L. B., & Corn, P. (2008) · Cell Cycle · doi:10.4161/cc.7.13.6203 · Cited by 69
“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…”
BackgroundInfluentialBunn, H. F. (2013) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a011619 · Cited by 234
“…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 85
“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 64
“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 62
“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 59
“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 77
Pietras, A., Johnsson, A. S., & Påhlman, S. (2010) · Current topics in microbiology and immunology · doi:10.1007/82_2010_72 · Cited by 62
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 63
“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 68
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
“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
Inherited predisposition to myeloproliferative neoplasms
Jones, A. V., & Cross, N. C. P. (2013) · Therapeutic Advances in Hematology · doi:10.1177/2040620713489144 · Cited by 58
Metadata
- 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 (clinical) › 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
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
