A novel heterozygous HIF2AM535I mutation reinforces the role of oxygen sensing pathway disturbances in the pathogenesis of familial erythrocytosis

Martini, Maurizio; Teofili, Luciana; Cenci, Tonia; Giona, Fiorina; Torti, Lorenza; Rea, Massimiliano; Foà, Robin; Leone, Giuseppe; Larocca, Luigi Maria

doi:10.3324/haematol.13210

Cited by 67 publications

(63 citation statements)

References 19 publications

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“…As EPAS1 is pleiotropic, other responses to hypoxia may be similarly affected. Some insight into these may be given by studies of a few individuals/families, living at low altitudes, who have been reported to have gain of function mutations in EPAS1 (37)(38)(39)(40). As expected, these individuals exhibit excessive erythrocytosis, but they also appear to be particularly susceptible to thrombotic events and to developing pulmonary hypertension-although the total number of cases reported is small.…”

Section: Discussionmentioning

confidence: 99%

Natural selection on EPAS1 ( HIF2α ) associated with low hemoglobin concentration in Tibetan highlanders

Beall

Cavalleri

Deng

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

717

770

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By impairing both function and survival, the severe reduction in oxygen availability associated with high-altitude environments is likely to act as an agent of natural selection. We used genomic and candidate gene approaches to search for evidence of such genetic selection. First, a genome-wide allelic differentiation scan (GWADS) comparing indigenous highlanders of the Tibetan Plateau (3,200-3,500 m) with closely related lowland Han revealed a genome-wide significant divergence across eight SNPs located near EPAS1. This gene encodes the transcription factor HIF2α, which stimulates production of red blood cells and thus increases the concentration of hemoglobin in blood. Second, in a separate cohort of Tibetans residing at 4,200 m, we identified 31 EPAS1 SNPs in high linkage disequilibrium that correlated significantly with hemoglobin concentration. The sex-adjusted hemoglobin concentration was, on average, 0.8 g/dL lower in the major allele homozygotes compared with the heterozygotes. These findings were replicated in a third cohort of Tibetans residing at 4,300 m. The alleles associating with lower hemoglobin concentrations were correlated with the signal from the GWADS study and were observed at greatly elevated frequencies in the Tibetan cohorts compared with the Han. High hemoglobin concentrations are a cardinal feature of chronic mountain sickness offering one plausible mechanism for selection. Alternatively, as EPAS1 is pleiotropic in its effects, selection may have operated on some other aspect of the phenotype. Whichever of these explanations is correct, the evidence for genetic selection at the EPAS1 locus from the GWADS study is supported by the replicated studies associating function with the allelic variants.chronic mountain sickness | high altitude | human genome variation | hypoxia | hypoxia-inducible factor

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Section: Discussionmentioning

confidence: 99%

Natural selection on EPAS1 ( HIF2α ) associated with low hemoglobin concentration in Tibetan highlanders

Beall

Cavalleri

Deng

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

717

770

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“…Recently, a similar phenotype of high erythropoietinassociated polycythemia without associated tumors has been reported in carriers of heterozygous germline mutations in the PHD2 and HIF-2A genes, [12][13][14][15][16][17][18][19] with the exception of one patient carrying a H374R-PHD2 mutation. 20 This particular patient simultaneously developed congenital secondary erythrocytosis and recurrent paraganglioma, a tumor originating from neural crest cells similar to pheochromocytoma but with an extra-adrenal localization.…”

Section: Introductionmentioning

confidence: 99%

Distinct deregulation of the hypoxia inducible factor by PHD2 mutants identified in germline DNA of patients with polycythemia

Ladroue

Hoogewijs²,

Gad³

et al. 2011

Haematologica

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BackgroundCongenital secondary erythrocytoses are due to deregulation of hypoxia inducible factor resulting in overproduction of erythropoietin. The most common germline mutation identified in the hypoxia signaling pathway is the Arginine 200-Tryptophan mutant of the von Hippel-Lindau tumor suppressor gene, resulting in Chuvash polycythemia. This mutant displays a weak deficiency in hypoxia inducible factor α regulation and does not promote tumorigenesis. Other von Hippel-Lindau mutants with more deleterious effects are responsible for von Hippel-Lindau disease, which is characterized by the development of multiple tumors. Recently, a few mutations in gene for the prolyl hydroxylase domain 2 protein (PHD2) have been reported in cases of congenital erythrocytosis not associated with tumor formation with the exception of one patient with a recurrent extra-adrenal paraganglioma. Design and MethodsFive PHD2 variants, four of which were novel, were identified in patients with erythrocytosis. These PHD2 variants were functionally analyzed and compared with the PHD2 mutant previously identified in a patient with polycythemia and paraganglioma. The capacity of PHD2 to regulate the activity, stability and hydroxylation of hypoxia inducible factor α was assessed using hypoxia-inducible reporter gene, one-hybrid and in vitro hydroxylation assays, respectively. ResultsThis functional comparative study showed that two categories of PHD2 mutants could be distinguished: one category with a weak deficiency in hypoxia inducible factor α regulation and a second one with a deleterious effect; the mutant implicated in tumor occurrence belongs to the second category. ConclusionsAs observed with germline von Hippel-Lindau mutations, there are functional differences between the PHD2 mutants with regards to hypoxia inducible factor regulation. PHD2 mutation carriers do, therefore, need careful medical follow-up, since some mutations must be considered as potential candidates for tumor predisposition.Key words: hypoxia inducible factor, hypoxia-inducible transcription factor, PHD2, erythrocytosis.Citation: Ladroue C, Hoogewijs D, Gad S, Carcenac R, Storti F, Barrois M, Gimenez-Roqueplo A-P, Leporrier M, Casadevall N, Hermine O, Kiladjian J-J, Baruchel A, Fakhoury F, Bressac-de Paillerets B, Feunteun J, Mazure N, Pouysségur J, Wenger RH, Richard S, and Gardie B. Distinct deregulation of the hypoxia inducible factor by PHD2 mutants identified in germline DNA of patients with polycythemia. Haematologica 2012;97(1):9-14.

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“…Families 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 2008aPercy et al ,b, 2012Furlow et al 2009;van Wijk et al 2010). These mutations generally impair the ability of HIF-2a to bind to VHL or PHD2.…”

Section: Overproduction Of Epomentioning

confidence: 99%

Erythropoietin

Bunn

2013

Cold Spring Harbor Perspectives in Medicine

208

171

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During the past century, few proteins have matched erythropoietin (Epo) in capturing the imagination of physiologists, molecular biologists, and, more recently, physicians and patients. Its appeal rests on its commanding role as the premier erythroid cytokine, the elegant mechanism underlying the regulation of its gene, and its remarkable impact as a therapeutic agent, arguably the most successful drug spawned by the revolution in recombinant DNA technology. This concise review will begin with a synopsis of the colorful history of this protein, culminating in its purification and molecular cloning. It then covers in more detail the contemporary understanding of Epo's physiology as well as its structure and interaction with its receptor. A major part of this article focuses on the regulation of the Epo gene and the discovery of HIF, a transcription factor that plays a cardinal role in molecular adaptation to hypoxia. In the concluding section, a synopsis of Epo's role in disorders of red blood cell production will be followed by an assessment of the remarkable impact of Epo therapy in the treatment of anemias, as well as concerns that provide a strong impetus for the development of even safer and more effective treatment.

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A novel heterozygous HIF2AM535I mutation reinforces the role of oxygen sensing pathway disturbances in the pathogenesis of familial erythrocytosis

Cited by 67 publications

References 19 publications

Natural selection on EPAS1 ( HIF2α ) associated with low hemoglobin concentration in Tibetan highlanders

Natural selection on EPAS1 ( HIF2α ) associated with low hemoglobin concentration in Tibetan highlanders

Distinct deregulation of the hypoxia inducible factor by PHD2 mutants identified in germline DNA of patients with polycythemia

Erythropoietin

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