Correspondence
The HIF2A Gene in Familial Erythrocytosis
N Engl J Med 2008; 358:1965-1967May 1, 2008
- Article
To the Editor:
Percy et al. (Jan. 10 issue)1 uncovered a mutation within the hypoxia-inducible factor 2α (HIF2A) gene as a cause of attenuated HIF-2α degradation and increased erythropoietin production in patients with familial erythrocytosis. This is an exciting observation, since studies on the relative contribution of HIF-1α and HIF-2α to hypoxia-driven gene expression are areas of intense investigation.2,3 A recent study of erythropoiesis in mice with tissue-specific deletion of Hif1a or Hif2a showed that hepatic erythropoietin production is preferentially regulated by Hif-2α.4 In contrast, renal erythropoietin appears to be regulated predominantly by Hif-1α.5 Do Percy et al. know whether familial erythrocytosis that is caused by a mutation of HIF2A increases erythropoiesis predominantly in the liver or the kidney?
5 ReferencesHolger K. Eltzschig, M.D., Ph.D.
Karim C. El Kasmi, M.D., Ph.D.
Tobias Eckle, M.D., Ph.D.
University of Colorado Health Sciences Center, Denver, CO 80262
holger.eltzschig@uchsc. edu 1
Percy MJ ,Furlow PW ,Lucas GS , et al. A gain-of-function mutation in the HIF2A gene in familial erythrocytosis. N Engl J Med 2008;358:162-168
Full Text | Web of Science | Medline2
Ratcliffe PJ . HIF-1 and HIF-2: working alone or together in hypoxia? J Clin Invest 2007;117:862-865
CrossRef | Web of Science | Medline3
Semenza GL . Life with oxygen. Science 2007;318:62-64
CrossRef | Web of Science | Medline4
Rankin EB ,Biju MP ,Liu Q , et al. Hypoxia-inducible factor-2 (HIF-2) regulates hepatic erythropoietin in vivo. J Clin Invest 2007;117:1068-1077
CrossRef | Web of Science | Medline5
Semenza GL . Regulation of mammalian O2 homeostasis by hypoxia-inducible factor 1. Annu Rev Cell Dev Biol 1999;15:551-578
CrossRef | Web of Science | Medline
To the Editor:
Percy et al. conclude that HIF-2α may be central to the regulation of erythropoietin levels, but HIF-1α was identified by its binding to a 3′ hypoxia-responsive element of the erythropoietin gene in the kidney,1 and severe anemia develops after nephrectomy. In contrast, the erythropoietin gene in the liver is regulated by upstream nucleotide sequences,2 and the liver produces only about 10 to 20% of the total erythropoietin. Alternative explanations for the phenotype described by Percy et al. are autonomous generation of erythropoietin by the liver (possibly with suppressed renal production of erythropoietin) or stimulation of transcription of the erythropoietin gene in the kidney and liver by the increased nitric oxide that accompanies the defect.3
The authors report that they increased the rate of phlebotomy in response to deep-vein thrombosis in the index patient. However, thrombosis that is associated with increased HIF-1α expression might be related to the altered expression of target genes that influence coagulation pathways4 rather than to polycythemia itself. Iron deficiency that is induced by phlebotomy could conceivably further increase HIF-1α levels5 and the risk of thrombosis.
5 ReferencesJosef T. Prchal, M.D.
University of Utah School of Medicine, Salt Lake City, UT 84132
josef.prchal@hsc. utah. edu Victor R. Gordeuk, M.D.
Howard University School of Medicine, Washington, DC 200601
Hirota K ,Semenza GL . Regulation of angiogenesis by hypoxia-inducible factor 1. Crit Rev Oncol Hematol 2006;59:15-26
CrossRef | Web of Science | Medline2
Semenza GL ,Koury ST ,Nejfelt MK ,Gearhart JD ,Antonarakis SE . Cell-type-specific and hypoxia-inducible expression of the human erythropoietin gene in transgenic mice. Proc Natl Acad Sci U S A 1991;88:8725-8729
CrossRef | Web of Science | Medline3
Johnson RS. Tissue-specific effects of HIF-1 loss of function. Presented at the Keystone Symposia on Molecular, Cellular, Physiological, and Pathogenic Responses to Hypoxia, Vancouver, BC, Canada, January 15–20, 2008.
4
Gordeuk VR ,Prchal JT . Vascular complications in Chuvash polycythemia. Semin Thromb Hemost 2006;32:289-294
CrossRef | Web of Science | Medline5
Peyssonnaux C ,Zinkernagel AS ,Schuepbach RA , et al. Regulation of iron homeostasis by the hypoxia-inducible transcription factors (HIFs). J Clin Invest 2007;117:1926-1932
CrossRef | Web of Science | Medline
To the Editor:
Percy et al. report an example of familial polycythemia, with inappropriately high erythropoietin levels due to a mutation of the gene that encodes HIF-2α. They conclude that this transcription factor, not HIF-1α, is the primary cause of the erythrocytosis in their patients. However, no analysis of the HIF1A gene was reported. We have investigated both HIF1A and HIF2A in 125 patients with familial erythrocytosis. We found that none of the patients had alterations in HIF1A and only one patient had a mutation of HIF2A. The change in the latter gene involved the same codon of HIF2A that was found by Percy et al., but it resulted in a different residue change (Gly537Arg). The absence of HIF1A mutations and the occurrence of a novel HIF2A mutation support the authors' conclusion that HIF-2α plays a pivotal role in the control of expression of the erythropoietin gene.
Silverio Perrotta, M.D.
Fulvio Della Ragione, M.D.
Second University of Naples, 80138 Naples, Italy
fulvio.dellaragione@unina2. it Author/Editor Response
Eltzschig et al. and Prchal and Gordeuk raise the issue of the source of erythropoietin in the family members with erythrocytosis whom we studied. Although we do not have direct evidence of the source in these patients, we believe that studies in genetically modified mice are relevant. Liver-specific deletion of Hif2α indicates that this isoform regulates erythropoietin production in the adult mouse liver.1 To the best of our knowledge, the corresponding cell-specific deletion experiment for erythropoietin-producing cells of the kidney has not been performed. However, Gruber and colleagues induced acute global deletion of both Hif1α and Hif2α in mice and found that the deletion of Hif2α, but not Hif1α, results in anemia.2 If Hif1α were the central isoform or merely a redundant isoform in the kidney, one might expect that Hif1α deletion would result in anemia or, at least, that the Hif2α deletion would not cause anemia. The observation that the Hif2α deletion does cause anemia indicates that this isoform is the critical regulator of erythropoietin. The point regarding the cause of the deep venous thrombosis is well taken and will require further investigation into the question of whether it might be mediated by HIF target genes.
Perrotta and Della Ragione state that they did not find evidence of any HIF1A mutation in their patients with erythrocytosis, a finding that is consistent with the results of a study we reported previously,3 but they did note an additional case of an erythrocytosis-associated mutation in the HIF2A gene. This observation is a further indication of the role played by HIF-2α in regulating erythropoietin in idiopathic erythrocytosis.
3 ReferencesMelanie J. Percy, Ph.D.
Belfast City Hospital, Belfast BT9 7AB, United KingdomGuy S. Lucas, M.D.
Manchester Royal Infirmary, Manchester M13 9WL, United KingdomFrank S. Lee, M.D., Ph.D.
University of Pennsylvania School of Medicine, Philadelphia, PA 19104
franklee@mail.med. upenn. edu 1
Rankin EB ,Biju MP ,Liu Q , et al. Hypoxia-inducible factor-2 (HIF-2) regulates hepatic erythropoietin in vivo. J Clin Invest 2007;117:1068-1077
CrossRef | Web of Science | Medline2
Gruber M ,Hu CJ ,Johnson RS ,Brown EJ ,Keith B ,Simon MC . Acute postnatal ablation of Hif-2α results in anemia. Proc Natl Acad Sci U S A 2007;104:2301-2306
CrossRef | Web of Science | Medline3
Percy MJ ,Mooney SM ,McMullin MF ,Flores A ,Lappin TR ,Lee FS . A common polymorphism in the oxygen-dependent degradation (ODD) domain of hypoxia inducible factor-1alpha (HIF-1α) does not impair Pro-564 hydroxylation. Mol Cancer 2003;2:31-31
CrossRef | Medline
