Novel exon 12 mutations in the HIF2A gene associated with erythrocytosis

Percy, Melanie J.; Beer, Philip; Campbell, Gavin; Dekker, Ad W.; Green, Anthony; Oscier, David; Rainey, Margaret; Wijk, Richard van; Wood, Marion; Lappin, Terence; McMullin, Mary Frances; Lee, Frank S.

doi:10.1182/blood-2008-02-137703

Cited by 117 publications

(113 citation statements)

References 19 publications

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“…Administration of exogenous EPO reverts this phenotype as well as some of the other defects associated with Hif2a elimination (Scortegagna et al 2005). Further supporting a role for HIF2A in EPO production, a gain-of-function mutation in the HIF2A gene has been found associated with familial erythrocytosis (Percy et al 2008a;Percy et al 2008b).…”

Section: Phenotypic Effects Of Hif-2α Eliminationmentioning

confidence: 84%

The HIF-2α-Driven Pseudo-Hypoxic Phenotype in Tumor Aggressiveness, Differentiation, and Vascularization

Pietras

Johnsson

Påhlman

2010

Current Topics in Microbiology and Immunology

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Section: Phenotypic Effects Of Hif-2α Eliminationmentioning

confidence: 84%

The HIF-2α-Driven Pseudo-Hypoxic Phenotype in Tumor Aggressiveness, Differentiation, and Vascularization

Pietras

Johnsson

Påhlman

2010

Current Topics in Microbiology and Immunology

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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.

731

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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“…144,145 . A point mutation in VHL leading to Chuvash polycythemia preferentially stabilizes HIF-2α 146 .…”

Section: Box 1: Timelinementioning

confidence: 99%

The impact of O2 availability on human cancer

2008

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During the last century, it has been established that regions within solid tumors experience mild to severe oxygen deprivation, due to aberrant vascular function. These hypoxic regions are associated with altered cellular metabolism, as well as increased resistance to radiation and chemotherapy. As discussed in this Timeline, over the past decade, work from many laboratories has elucidated the mechanisms by which hypoxia-inducible factors (HIFs) modulate tumor cell metabolism, angiogenesis, growth, and metastasis. The central role played by intra-tumoral hypoxia and HTF in these processes has made them attractive therapeutic targets in the treatment of multiple human malignancies.Oxygen (O 2 ) is required for aerobic metabolism to maintain intracellular bioenergetics and serve as an electron acceptor in many organic and inorganic reactions. Hypoxia, defined as reduced O 2 levels, occurs in a variety of pathological conditions, including stroke, tissue ischemia, inflammation, and the growth of solid tumors. The beginnings of hypoxia research in tumor biology can be traced back to observations made in the early 20 th century by Otto Warburg who demonstrated that, unlike normal cells, tumor cells favor glycolysis, independent of cellular oxygenation levels. He postulated that tumor growth is caused by mitochondrial dysfunction in neoplastic cells, forcing them to generate energy through glycolysis (reviewed in 1 ). This hypothesis appears to be incorrect, but a number of other molecular mechanisms promoting "aerobic glycolysis" have been proposed including mutations and epigenetic changes in genes encoding tumor suppressors (e.g. p53), oncogene activation (e.g. c-Myc), and hypoxic adaptations {Denko, 2008 #6606; Gatenby, 2004 #6608; Deberardinis, 2008 #6609.

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Novel exon 12 mutations in the HIF2A gene associated with erythrocytosis

Cited by 117 publications

References 19 publications

The HIF-2α-Driven Pseudo-Hypoxic Phenotype in Tumor Aggressiveness, Differentiation, and Vascularization

The HIF-2α-Driven Pseudo-Hypoxic Phenotype in Tumor Aggressiveness, Differentiation, and Vascularization

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

The impact of O2 availability on human cancer

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