Two new mutations in the <i>HIF2A</i> gene associated with erythrocytosis

Percy, Melanie J.; Chung, Yong; Harrison, Claire; Mercieca, Jane; Hoffbrand, A. V.; Dinardo, Carla Luana; Santos, P. Marques Dos; Fonseca, Guilherme Henrique Hencklain; Gualandro, Sandra Fátima Menosi; Pereira, Alexandre C.; Lappin, Terrance R.J.; McMullin, Mary Frances; Lee, Frank S.

doi:10.1002/ajh.23123

Cited by 38 publications

(35 citation statements)

References 25 publications

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“…[34][35][36][37][38][39][40][41] Similar data were reported in other studies on HIF2A-dependent polycythemias although scarce attention has been paid to this finding. [37][38][39][40][41][42][43][44] So far seven patients, including the case reported here, have been found to have the Gly537Arg HIF2A mutation. Three patients belong to the same family.…”

supporting

confidence: 74%

“…[29][30][31][32][33][34][35][36][37][38][39][40][41] The genetic changes embrace homozygous or compound heterozygous mutations of the VHL gene, heterozygous PHD2 gene changes, and heterozygous mutations of the HIF2A gene. [29][30][31][32][33][34][35][36][37][38][39][40][41] Specific HIF2A and PHD2 haplotypes have also been associated with adaptation to high altitudes in Tibetans, confirming the central role of these genes in the hypoxic response. [42][43][44] Interestingly, no mutation of HIF1A has been reported so far.…”

Section: Introductionmentioning

confidence: 99%

“…35,45 Mechanistically, PHD2 and VHL mutations lead to loss of function of the respective proteins, while HIF2A mutations probably lead to a gain of function of HIF-2α. [29][30][31][32][33][34][35][36][37][38][39][40][41] A small number of subjects affected by inherited HIF2A mutations (Pro534Leu, Met535Val, Met535Ile, Met535Thr, Gly537Trp, Gly537Arg, Asp539Glu, Phe540Leu) in heterozygosity have been described. These patients show a dominant erythrocytosis and increased or inappropriately normal EPO serum levels.…”

Section: Introductionmentioning

confidence: 99%

“…These patients show a dominant erythrocytosis and increased or inappropriately normal EPO serum levels. [34][35][36][37][38][39][40][41] In some cases, the patients present a history of thrombosis or pulmonary hypertension. 35 Increased serum EPO is supposed to be the cause of erythrocytosis in these patients.…”

Section: Introductionmentioning

confidence: 99%

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Congenital erythrocytosis associated with gain-of-function HIF2A gene mutations and erythropoietin levels in the normal range

et al. 2013

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Hypoxia-inducible factor 2α (HIF-2α) plays a pivotal role in the balancing of oxygen requirements throughout the body. The protein is a transcription factor that modulates the expression of a wide array of genes and, in turn, controls several key processes including energy metabolism, erythropoiesis and angiogenesis. We describe here the identification of two cases of familial erythrocytosis associated with heterozygous HIF2A missense mutations, namely Ile533Val and Gly537Arg. Ile533Val is a novel mutation and represents the genetic HIF2A change nearest to Pro-531, the primary hydroxyl acceptor residue, so far identified. The Gly537Arg missense mutation has already been described in familial erythrocytosis. However, our patient is the only described case of a de novo HIF2A mutation associated with the development of congenital polycythemia. Functional in vivo studies, based on exogenous expression of hybrid HIF-2α transcription factors, indicated that these genetic alterations lead to the stabilization of HIF-2α protein. All the identified polycythemic subjects with HIF2A mutations show serum erythropoietin in the normal range, independently of the hematocrit values and phlebotomy frequency. The erythroid precursors obtained from the peripheral blood of patients showed an altered phenotype, including an increased rate of growth and a modified expression of some HIF-2α target genes. These results suggest the novel proposal that polycythemia observed in subjects with HIF2A mutations might also be due to primary changes in hematopoietic cells and not only secondary to increased erythropoietin levels. Congenital erythrocytosis associated with gain-of-function HIF2A gene mutations and erythropoietin levels in the normal range

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supporting

confidence: 74%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Congenital erythrocytosis associated with gain-of-function HIF2A gene mutations and erythropoietin levels in the normal range

et al. 2013

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“…In these cases, PHDs or other HIF suppression systems might be disrupted in the malignant cells. Recently, hereditary polycythemia has been linked to mutations in the PHD2 and HIF2␣ genes (59)(60)(61)(62)(63), indicating that a PHD-HIF2␣ pathway regulates EPO gene expression in humans.…”

Section: Discussionmentioning

confidence: 99%

Hypoxia Signaling Cascade for Erythropoietin Production in Hepatocytes

Tojo

Sekine

Hirano

et al. 2015

Molecular and Cellular Biology

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f Erythropoietin (Epo) is produced in the kidney and liver in a hypoxia-inducible manner via the activation of hypoxia-inducible transcription factors (HIFs) to maintain oxygen homeostasis. Accelerating Epo production in hepatocytes is one plausible therapeutic strategy for treating anemia caused by kidney diseases. To elucidate the regulatory mechanisms of hepatic Epo production, we analyzed mouse lines harboring liver-specific deletions of genes encoding HIF-prolyl-hydroxylase isoforms (PHD1, PHD2, and PHD3) that mediate the inactivation of HIF1␣ and HIF2␣ under normal oxygen conditions. The loss of all PHD isoforms results in both polycythemia, which is caused by Epo overproduction, and fatty livers. We found that deleting any combination of two PHD isoforms induces polycythemia without steatosis complications, whereas the deletion of a single isoform induces no apparent phenotype. Polycythemia is prevented by the loss of either HIF2␣ or the hepatocyte-specific Epo gene enhancer (EpoHE). Chromatin analyses show that the histones around EpoHE dissociate from the nucleosome structure after HIF2␣ activation. HIF2␣ also induces the expression of HIF3␣, which is involved in the attenuation of Epo production. These results demonstrate that the total amount of PHD activity is more important than the specific function of each isoform for hepatic Epo expression regulated by a PHD-HIF2␣-EpoHE cascade in vivo.

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Genetic Basis of Congenital Erythrocytosis: Mutation Update and Online Databases

et al. 2013

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Congenital Erythrocytosis (CE), also called congenital polycythemia, represents a rare and heterogeneous clinical entity. It is caused by deregulated red blood cell production where erythrocyte overproduction results in elevated hemoglobin and hematocrit levels. 3Primary congenital familial erythrocytosis is associated with low erythropoietin (Epo) levels and generally results from mutations in the erythropoietin-receptor gene (EPOR).Secondary congenital erythrocytosis arises from conditions which cause tissue hypoxia thus resulting in increased Epo production. These include hemoglobin variants with increased affinity for oxygen (genes HBB, HBA1 and HBA2), decreased production of 2,3-biphosphoglycerate due to mutations in the BPGM gene, or mutations in the genes involved in the hypoxia sensing pathway (VHL, EPAS1 and EGLN1). Depending on the affected gene CE can be inherited either in an autosomal dominant or recessive mode, with sporadic cases arising de novo.Despite recent important discoveries in the molecular pathogenesis of CE, the molecular causes remain to be identified in about 70% of the patients.With the objective of collecting all the published and unpublished cases of CE the COST action MPN&MPNr-Euronet developed a comprehensive internet-based database focusing on the registration of clinical history, hematological, biochemical and molecular data (http://www.erythrocytosis.org/). In addition, unreported mutations are also curated in the corresponding Leiden Open Variation Database (LOVD).

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Two new mutations in the HIF2A gene associated with erythrocytosis

Cited by 38 publications

References 25 publications

Congenital erythrocytosis associated with gain-of-function HIF2A gene mutations and erythropoietin levels in the normal range

Congenital erythrocytosis associated with gain-of-function HIF2A gene mutations and erythropoietin levels in the normal range

Hypoxia Signaling Cascade for Erythropoietin Production in Hepatocytes

Genetic Basis of Congenital Erythrocytosis: Mutation Update and Online Databases

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