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A Gain-of-Function Mutation in the HIF2A Gene in Familial Erythrocytosis
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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, 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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“particular mutation results in stabilization of HIF2A due to impaired hydroxylation.(95) HIF2A mutations may be associated with neuroendocrine tumors with a genotype/phenotype study illustrating the clinical”
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JAK2 unmutated erythrocytosis: current diagnostic approach and therapeutic views
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“Induction of downstream genes is significantly increased by the mutation.(23) A different amino acid change at 537, Gly537Arg,(24) and two mutations at 535, Met535Val(25) and Met535Ile,(26) and a Pro534Leu mutation(27) have been identified.”
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“Stabilization of HIF-2α, caused by a gain-of-function germline mutation in the HIF-2α gene (EPAS1), leads to familial erythrocytosis and germline mutations of PHD2 induce erythrocytosis and elevated EPO levels [21, 22].”
BackgroundCurrent Management of Sickle Cell AnemiaPreprint
McGann, P. T., Nero, A. C., & Ware, R. E. (2013) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a011817 · Cited by 54
“…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).”
Graham, A. M., & McCracken, K. G. (2019) · Heredity · doi:10.1038/s41437-018-0173-z · Cited by 57
“Such gain-offunction mutations are known to cause erythrocytosis, resulting in an increased number of RBCs through its regulation of erythropoietan, in combination with pulmonary arterial hypertension, in humans (Gale et al. 2008; Percy et al. 2008a; Percy et al. 2008b).”
BackgroundSeeley, T. W., Sternlicht, M. D., Klaus, S. J., Neff, T. B., & Liu, D. Y. (2017) · Hypoxia · doi:10.2147/hp.s130526 · Cited by 54
Modulation of the Hypoxic Response
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The role of PHD2 mutations in the pathogenesis of erythrocytosis
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“previously, mutations in the EPAS1 gene are another cause of erythrocytosis.(102) The Epo levels in the Phd2P294R/+ mice, as in the Phd2+/-”
Self-citationAdvances in understanding the pathogenesis of primary familial and congenital polycythaemia
Huang, L. J.-S., Shen, Y.-M. P., & Bulut, G. B. (2010) · British Journal of Haematology · doi:10.1111/j.1365-2141.2009.08069.x · Cited by 52
“…of the oxygen sensing mechanism, such as the hypoxia-inducible factor (HIF), EGLN/HPH/PHD family of HIF-prolyl hydroxylases, and von Hippel-Lindau tumour suppressor protein (VHL) (Gordeuk et al, 2005; Percy et al, 2006, 2007, 2008; Al-Sheikh et al, 2008a; Ladroue et al, 2008; Martini et al, 2008).”
BackgroundHIF Signaling Pathway in Pheochromocytoma and Other Neuroendocrine Tumors
Jochmanová, I., Zelinka, T., Widimsky, J., Jr., & Pacák, K. (2014) · Physiological Research · doi:10.33549/physiolres.932789 · Cited by 49
“Previously, dominantly inherited gain-offunction HIF2A mutations were found to be associated with congenital polycythemia (Percy et al. 2008, Prchal and Gordeuk 2008), which stresses the role of HIF-2α in the regulation of erythropoiesis.”
BackgroundBai, J., Li, L., Li, Y., & Zhang, L. (2022) · Environmental Health and Preventive Medicine · doi:10.1265/ehpm.22-00040 · Cited by 53
Hypoxia-inducible factor stabilizers for treating anemia of chronic kidney disease
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“Gain-of-function mutations in the EPAS1 gene that encodes HIF2A have been reported in families with erythrocytosis, inherited in an autosomal dominant fashion [37,42].”
BackgroundTwo functional loci in the promoter of EPAS1 gene involved in high-altitude adaptation of Tibetans
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Hypoxia Regulates BMP4 Expression in the Murine Spleen during the Recovery from Acute Anemia
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“Although HIF-1 was originally isolated as the factor responsible for EPO induction, it has in the meantime been shown that EPO is a target of HIF-2 [52,53].”
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Pang, Y. K., Liu, Y., Pacák, K., & Yang, C. (2019) · Cancers · doi:10.3390/cancers11040436 · Cited by 48
“Mutations in HIF2A have been identified in human diseases such as polycythemia, PCPG and somatostatinoma [42,43].”
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Petousi, N., Copley, R. R., Lappin, T. R. J., Haggan, S. E., Bento, C., Cario, H., Percy, M. J., Ratcliffe, P. J., Robbins, P. A., McMullin, M. F., et al. (2014) · Haematologica · doi:10.3324/haematol.2014.109306 · Cited by 59
“expressed (His)6FlagPHD2 (20) as described previously ( 13 ).”
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“The recent identification of a mutation in the HIF-2 gene that is associated with congenital erythrocytosis suggests that variation within the HIF genes themselves could be one source of variation (37).”
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Lee, F. S. (2008) · Blood Reviews · doi:10.1016/j.blre.2008.04.003 · Cited by 43
“Functionally, this mutation significantly impairs the ability of HIF-2a to be recognized by PHD2, its capacity to be hydroxylated by PHD2, and its ability to be recognized by VHL following hydroxylation.(82) Interestingly, the phenotype in this family bears similarity to that of Chuvash polycythemia, in which there ar…”
BackgroundSelf-citationGenomic Analyses Reveal Genetic Adaptations to Tropical Climates in Chickens
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“Evidence for a central role for HIF-2α in erythropoiesis is also provided by patients with protein-stabilizing missense mutations in the HIF2A gene (36).”
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Updates on Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitors in the Treatment of Renal Anemia
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Erythrocytosis associated with a novel missense mutation in the HIF2A gene
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“In vitro assays pcDNA3-GAL4-HIF-2α (516-549) has been described previously.(13) pcDNA3-GAL4-HIF-2α (516-549) D539E was constructed by subcloning into the Eco RI/Xba I site of pcDNA3-GAL4 an oligonucleotide duplex comprised of the following sequences: 5’-AAT TCA GTA CCC AGA CGG ATT TCA ATG AGC TGG ACT TGG AGA CAC TGG C…”
BackgroundMethodInfluentialSelf-citationThe VHL/HIF Axis in the Development and Treatment of Pheochromocytoma/Paraganglioma
Song, P., Zhang, J., Tan, X., Huang, Y., Xu, J., Silk, N., Zhang, D., Liu, Q., & Jiang, J. (2020) · Frontiers in Endocrinology · doi:10.3389/fendo.2020.586857 · Cited by 42
“Gly537Trp only leads to polycythemias, not tumors (64, 65).”
BackgroundHIF Activation Against CVD in CKD: Novel Treatment Opportunities
Tanaka, T., & Eckardt, K. (2018) · Seminars in Nephrology · doi:10.1016/j.semnephrol.2018.02.006 · Cited by 40
Advances in understanding the pathogenesis of familial myeloproliferative neoplasms
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Two new mutations in the HIF2A gene associated with erythrocytosis
Percy, M. J., Chung, Y. J., Harrison, C., Mercieca, J., Hoffbrand, A. V., Dinardo, C. L., Santos, P. C. J. L., Fonseca, G. H. H., Gualandro, S. F. M., Pereira, A. C., et al. (2012) · American Journal of Hematology · doi:10.1002/ajh.23123 · Cited by 37
“PCR-direct sequencing was performed for exon 12 of HIF2A as described previously [13].”
MethodSelf-citationFunctional EPAS1 / HIF2A missense variant is associated with hematocrit in Andean highlanders
Lawrence, E. S., Gu, W., Bohlender, R. J., Anza‐Ramirez, C., Cole, A. M., Yu, J. J., Hu, H., Heinrich, E. C., O’Brien, K. A., Vasquez, C. A., et al. (2024) · Science Advances · doi:10.1126/sciadv.adj5661 · Cited by 41
“The genes used for quantitative real-time PCR (table S5) were assayed in prior studies assessing HIF-2 activity ( 84 – 87 ).”
MethodLi, S., Li, W., Yuan, J., Bullova, P., Wu, J., Zhang, X., Liu, Y., Plescher, M., Rodríguez, J., Bedoya-Reina, O. C., et al. (2022) · Nature Metabolism · doi:10.1038/s42255-022-00593-x · Cited by 36
“Although HIF2 α is considered to be an oncogenic driver in VHL -related ccRCC, familial gain-of-function HIF2a mutations have only been reported to be associated with familial erythrocy-tosis 44 .”
Fukui, K., Shinozaki, Y., Kobayashi, H., Deai, K., Yoshiuchi, H., Matsui, T., Matsuo, A., Matsushita, M., Tanaka, T., & Nangaku, M. (2019) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2019.172532 · Cited by 45
Targeting EPO and EPO receptor pathways in anemia and dysregulated erythropoiesis
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“Via conditional gene disruption studies in mice, PHD2 is emerging as one prime modulator of HIF2a expression in renal EPO producing cells [6,63,68-72].”
BackgroundThe Genetics of Altitude Tolerance
MacInnis, M. J., Wang, P., Koehle, M. S., & Rupert, J. L. (2011) · Journal of Occupational and Environmental Medicine · doi:10.1097/jom.0b013e318206b112 · Cited by 34
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“EPAS1 (HIF2A) gain-of-function mutations are characterized by reduced binding efficiency to the HIF-α inhibitor PHD2, decreased ubiquitination, increased HIF-2α stability, and increased transcription of HIF-regulated genes in granulocytes.(17) Over the last two decades, we (JTP and FRL) studied a six-generation pedigr…”
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Diagnosis and management of congenital and idiopathic erythrocytosis
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“…mutations have been described that result in erythrocytosis in those with homozygous or compound heterozygous mutations in the VHL gene [Ang et al. 2002], heterozygote mutations in the PHD2 gene [Percy et al. 2006], and heterozygote mutations in the HIF2A gene [Percy et al. 2008; McMullin, 2010].”
BackgroundSelf-citationHIF pathway mutations and erythrocytosis
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Self-citationA Transgenic Mouse Model of Pacak–Zhuang Syndrome with An Epas1 Gain-of-Function Mutation
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HIF-2α-pVHL complex reveals broad genotype-phenotype correlations in HIF-2α-driven disease
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“0001) and had lower serum ferritin concentrations (geometric mean [SD range] values of 10 [3-32] vs.”
BackgroundGenetic origins and clinical phenotype of familial and acquired erythrocytosis and thrombocytosis
Percy, M. J., & Rumi, E. (2008) · American Journal of Hematology · doi:10.1002/ajh.21313 · Cited by 30
“The first HIF-2a mutation, Gly537Trp, was reported in three affected members from the same family over three generations [27].”
BackgroundSelf-citationHypoxia Inducible Factor pathway proteins in high-altitude mammals
Lee, F. S. (2023) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2023.11.002 · Cited by 31
Self-citationHypoxia Signaling in Vascular Homeostasis
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“For example, a heterozygous G1609- T mutation in exon 12 of HIF-2 was identified in a family with erythrocytosis, and the resulting amino acid change led to a weaker binding of PHD2 to Pro531 and reduced degradation of HIF-2 (57).”
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“disease.[52,53] Although the effect is mainly mediated by an aberrant systemic increase of EPO, likely to be produced by kidney cells, mutated hematopoietic pro-”
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Population History and Altitude-Related Adaptation in the Sherpa
Bhandari, S., & Cavalleri, G. L. (2019) · Frontiers in Physiology · doi:10.3389/fphys.2019.01116 · Cited by 40
Li, C., Li, X., Xiao, J., Liu, J., Xiu, F., Fan, F., & Lei, H. (2019) · PeerJ · doi:10.7717/peerj.7943 · Cited by 31
“Studies have shown that EPAS1 gene expression is also associated 297 with EPO levels (Lee & Percy 2011; Percy et al. 2008).”
BackgroundSelf-citationMcMullin, M. F. (2016) · International Journal of Laboratory Hematology · doi:10.1111/ijlh.12506 · Cited by 24
Self-citationThe role of the ubiquitin–proteasome system in kidney diseases
Fukasawa, H. (2012) · Clinical and Experimental Nephrology · doi:10.1007/s10157-012-0643-1 · Cited by 25
“In humans, a mutation of HIF-a that stabilizes HIF-2a was shown to be a cause of familial erythrocytosis [94].”
BackgroundThe 2019 Nobel Prize honors fundamental discoveries in hypoxia response
Moslehi, J., & Rathmell, W. K. (2019) · Journal of Clinical Investigation · doi:10.1172/jci134813 · Cited by 25
A pleiotropic hypoxia-sensitive EPAS1 enhancer is disrupted by adaptive alleles in Tibetans
Gray, O. A., Yoo, J., Sobreira, D. R., Jousma, J., Witonsky, D., Sakabe, N. J., Peng, Y., Prabhakar, N. R., Fang, Y. H., Nóbrega, M. A., et al. (2022) · Science Advances · doi:10.1126/sciadv.ade1942 · Cited by 33
Polycythemia and Paraganglioma With a Novel Somatic HIF2A Mutation in a Male
Toyoda, H., Hirayama, J., Sugimoto, Y., Uchida, K., Ohishi, K., Hirayama, M., & Komada, Y. (2014) · PEDIATRICS · doi:10.1542/peds.2013-2419 · Cited by 29
Lai, Y., Qiao, M., Song, M., Weintraub, S. T., & Shiio, Y. (2011) · PLoS ONE · doi:10.1371/journal.pone.0016975 · Cited by 23
Dual-functional probes for sequential thiol and redox homeostasis sensing in live cells
Ma, T., Ding, H., Xu, H., Lv, Y., Liu, H., Wang, H., & Tian, Z. (2014) · The Analyst · doi:10.1039/c4an01441c · Cited by 25
Zheng, Z. L., Hwang, Y., Kim, S. K., Kim, S., Son, M. J., Ro, H., Sung, S.-A., Lee, H. H., Chung, W. K., Joo, K. W., et al. (2009) · Nephron Clinical Practice · doi:10.1159/000228542 · Cited by 24
Arsenault, P. R., Song, D., Chung, Y. J., Khurana, T. S., & Lee, F. S. (2016) · Molecular and Cellular Biology · doi:10.1128/mcb.00090-16 · Cited by 24
“HA-HIF-1α HA-HIF-1α-BAP HA-FKBP51 HA-FKBP51-BAP Flag-PHD2(1-196)-BirA”
MethodInfluentialSelf-citationSomatic gain-of-function HIF2A mutations in sporadic central nervous system hemangioblastomas
Taïeb, D., Barlier, A., Yang, C., Pertuit, M., Tchoghandjian, A., Rochette, C., Zattara-Canoni, H., Figarella‐Branger, D., Zhuang, Z., Pacák, K., et al. (2015) · Journal of Neuro-Oncology · doi:10.1007/s11060-015-1983-y · Cited by 21
“Germline mutations in the HIF2A (EPAS1) gene (hypoxia-inducible factor 2a) have been associated with congenital polycythemia [19].”
BackgroundMutations profile of polycythemia vera and essential thrombocythemia among Japanese children
Ismael, O., Shimada, A., Hama, A., Sakaguchi, H., Doisaki, S., Muramatsu, H., Yoshida, N., Ito, M., Takahashi, Y., Akita, N., et al. (2011) · Pediatric Blood & Cancer · doi:10.1002/pbc.23409 · Cited by 20
Genetic basis of unexplained erythrocytosis in Indian patients
Mallik, N., Sharma, P., Hira, J. K., Chhabra, S., Sreedharanunni, S., Kumar, N., Naseem, S., Sachdeva, M. U. S., Ahluwalia, J., Malhotra, P., et al. (2019) · European Journal Of Haematology · doi:10.1111/ejh.13267 · Cited by 21
Rogers, H. M., Wang, L., Yu, X., Alnaeeli, M., Cui, K., Zhao, K., Bieker, J. J., Prchal, J. T., Huang, S., Weksler, B. B., et al. (2012) · Journal of Biological Chemistry · doi:10.1074/jbc.m112.378398 · Cited by 18
Pang, Y. K., Gupta, G., Jha, A., Yue, X., Wang, H., Huynh, T., Li, A., Li, L., Baker, E. H., Chew, E. Y., et al. (2019) · Cancer · doi:10.1002/cncr.31839 · Cited by 21
“Age at PHEO/PGL diagnosis, y, median (range) 34 (30-55) 17 (8-38)”
GUO, L., Zhang, J., Jin, J., Gao, X., Yu, J., GENG, Q., Li, H., & Huang, L. J. (2015) · Experimental and Therapeutic Medicine · doi:10.3892/etm.2015.2611 · Cited by 21
Parsad, R., Ahlawat, S., Bagiyal, M., Arora, R., Gera, R., Chhabra, P., Sharma, U., & Singh, A. (2024) · Mammalian Genome · doi:10.1007/s00335-024-10101-z · Cited by 19
“EPAS1 (also known as HIF2A ) regulates erythropoietin production, affecting hemoglobin levels, and codes for the hypoxia-inducible transcription factor HIF-2α (Percy et al. 2008).”
Mutations in EPAS1 in congenital heart disease in Tibetans
Pan, H., Chen, Q., Qi, S., Li, T., Liu, B., Liu, S., Ma, X., & Wang, B. (2018) · Bioscience Reports · doi:10.1042/bsr20181389 · Cited by 18
Jacob, E. (2016) · doi:10.11648/j.ajlm.20160103.12 · Cited by 19
“These conditions are relatively uncommon[19, 20, 21, 22, 23] Conditions where the secondary polycythemia is not as a result of physiologic adaptation and occurs irrespective of body needs include: Neoplasms - Renal-cell carcinoma or liver tumors, von Hippel-Lindau disease, and endocrine abnormalities including pheochr…”
BackgroundInfluentialErythropoietic Agents and the Elderly
Agarwal, N., & Prchal, J. T. (2008) · Seminars in Hematology · doi:10.1053/j.seminhematol.2008.06.007 · Cited by 16
High-Altitude Andean H194R HIF2A Allele Is a Hypomorphic Allele
Jorgensen, K. C., Song, D., Weinstein, J. B., Garcia, O. A., Pearson, L. N., Inclán, M., Rivera, M. C., Lèon‐Velarde, F., Kiyamu, M., Brutsaert, T. D., et al. (2023) · Molecular Biology and Evolution · doi:10.1093/molbev/msad162 · Cited by 18
“The HIF-2α constructs were prepared in the context of a P531A mutation that abolishes the primary site of prolyl hydroxylation and thereby stabilizes the HIF-2α under normoxia (Percy et al. 2008).”
BackgroundSelf-citationZhao, Y., Zhang, Z., Liu, L., Zhang, Y., Fan, X., Ma, L., Li, J., Zhang, Y., He, H., & Kang, L. (2017) · Oncotarget · doi:10.18632/oncotarget.21420 · Cited by 19
“Frank et al [23] reported the HIF has been implicated as the primary regulator of erythropoietin.”
BackgroundPainschab, M., Malpartida, G., Dávila‐Román, V. G., Gilman, R. H., Kolb, T. M., Lèon‐Velarde, F., Miranda, J. J., & Checkley, W. (2015) · High Altitude Medicine & Biology · doi:10.1089/ham.2014.1086 · Cited by 21
“Mutations have been found in HIF2A, EGLN1, and VHL genes that promote HIF2a stability and HIF-dependent gene expression (Percy et al., 2008) and are correlated with erythrocytosis and elevations in pulmonary arterial pressures (Semenza, 2011; Shimoda and Laurie, 2014).”
BackgroundOxygen Sensing, Homeostasis, and Disease
Bels, D. D., Corazza, F., & Balestra, C. (2011) · New England Journal of Medicine · doi:10.1056/nejmc1110602
Diagnostic workflow for hereditary erythrocytosis and thrombocytosis
McMullin, M. F. (2019) · Hematology · doi:10.1182/hematology.2019000047 · Cited by 21
Self-citationPang, Y. K., Gupta, G., Yang, C., Wang, H., Huynh, T., Abdullaev, Z., Pack, S., Percy, M. J., Lappin, T. R. J., Zhuang, Z., et al. (2018) · BMC Cancer · doi:10.1186/s12885-018-4127-x · Cited by 20
Self-citationHereditary erythrocytosis, thrombocytosis and neutrophilia
Hong, W., & Gotlib, J. R. (2014) · Best Practice & Research Clinical Haematology · doi:10.1016/j.beha.2014.07.002 · Cited by 25
“In vitro assays showed decrease in binding of PHD2 to the HIF2a G537W mutant compared to wild type as well as decrease in hydroxylation of the mutant HIF-2a [43].”
MethodThe interaction of the von Hippel-Lindau tumor suppressor and heterochromatin protein 1
Lai, Y., Song, M., Hakala, K. W., Weintraub, S. T., & Shiio, Y. (2012) · Archives of Biochemistry and Biophysics · doi:10.1016/j.abb.2011.12.023 · Cited by 15
Karaghiannis, V., Maric, D., Garrec, C., Maaziz, N., Buffet, A., Schmitt, L., Antunes, V., Airaud, F., Aral, B., Roy, A. L., et al. (2023) · Haematologica · doi:10.3324/haematol.2022.281698 · Cited by 17
Zheng, Q., Wang, Y., Yang, H., Sun, L., Fu, X., Wei, R., Liu, Y., & Liu, W. J. (2021) · Frontiers in Pharmacology · doi:10.3389/fphar.2020.573645 · Cited by 17
“A missense mutation in the HIF-α gene was discovered in patients with familial erythrocytosis and has been found to lead to stabilization of the HIF-α protein (Percy et al., 2008).”
BackgroundHereditary gene mutations in Korean patients with isolated erythrocytosis
Jang, J., Seo, J. Y., Jang, J., Jung, C. W., Lee, K.-O., Kim, S., & Kim, H. (2014) · Annals of Hematology · doi:10.1007/s00277-014-2006-3 · Cited by 13
A large‐scale replication study for the association of rs17039192 in HIF‐2α with knee osteoarthritis
Nakajima, M., Shi, D., Dai, J., Tsezou, A., Zheng, M., Norman, P., Chou, C., Lee, M., Hwang, J.-Y., Kim, D.-H., et al. (2012) · Journal of Orthopaedic Research · doi:10.1002/jor.22063 · Cited by 16
“HIF-2a mutations are associated with erythrocytosis familial type 4.(1) The genetic association of single nucleotide polymorphisms (SNPs) in HIF-2a has been investigated in various diseases and phenotypes.”
BackgroundReview article: How cells sense oxygen: Lessons from and for the kidney
Gleadle, J. (2009) · Nephrology · doi:10.1111/j.1440-1797.2008.01064.x · Cited by 18
“This has been revealed by studies using siRNA techniques,(52) in mice with targeted disruptions of the HIF genetic loci and in observations in humans with genetic polycythaemia.(56,57) Interestingly, it also seems to have a more important role in the generation of renal cancer in VHL mutation.”
MethodHyperoxia Alters Ultrastructure and Induces Apoptosis in Leukemia Cell Lines
Bels, D. D., Tillmans, F., Corazza, F., Bizzarri, M., Germonpré, P., Radermacher, P., Orman, K. G., & Balestra, C. (2020) · Biomolecules · doi:10.3390/biom10020282 · Cited by 18
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
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