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EPAS1 gene

endothelial PAS domain protein 1
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Normal Function

The EPAS1 gene, often known as HIF2A, provides instructions for making a protein called hypoxia-inducible factor 2-alpha (HIF-2α). This protein is one part (subunit) of a larger protein complex called HIF, which plays a critical role in the body's ability to adapt to changing oxygen levels. HIF controls several important genes involved in cell division, the formation of new blood vessels, and the production of red blood cells. It is the major regulator of a hormone called erythropoietin, which controls red blood cell production.

HIF-2α is constantly produced in the body. When adequate oxygen is available, other proteins target HIF-2α to be broken down (degraded) so it does not build up. However, when oxygen levels are lower than normal (hypoxia), HIF-2α is degraded at a slower rate. Consequently, more HIF is available to stimulate the formation of new blood vessels and the production of red blood cells. These activities help maximize the amount of oxygen that can be delivered to the body's organs and tissues.

Studies suggest that the EPAS1 gene is involved in the body's adaptation to high altitude. At higher altitudes, such as in mountainous regions, air pressure is lower and less oxygen enters the body through the lungs. Over time, the body compensates for the lower oxygen levels by changing breathing patterns and producing more red blood cells and blood vessels.

Health Conditions Related to Genetic Changes

Familial erythrocytosis

At least five mutations in the EPAS1 gene have been found to cause familial erythrocytosis, an inherited condition characterized by an increased number of red blood cells and an elevated risk of abnormal blood clots. When familial erythrocytosis results from EPAS1 gene mutations, it is often designated ECYT4.

Mutations in the EPAS1 gene change single protein building blocks (amino acids) in the HIF-2α protein. These changes prevent HIF-2α from interacting normally with the proteins that target it for degradation. As a result, HIF-2α is not degraded efficiently, and HIF accumulates in cells even when adequate oxygen is available. The presence of extra HIF leads to the production of red blood cells when no more are needed, resulting in an excess of these cells in the bloodstream.

More About This Health Condition

Other Names for This Gene

  • basic-helix-loop-helix-PAS protein MOP2
  • bHLHe73
  • class E basic helix-loop-helix protein 73
  • ECYT4
  • endothelial PAS domain-containing protein 1
  • EPAS-1
  • EPAS1_HUMAN
  • HIF-1-alpha-like factor
  • HIF-1alpha-like factor
  • HIF-2-alpha
  • HIF2-alpha
  • HIF2A
  • HLF
  • hypoxia-inducible factor 2 alpha
  • hypoxia-inducible factor 2-alpha
  • member of PAS protein 2
  • MOP2
  • PAS domain-containing protein 2
  • PASD2

Additional Information & Resources

Tests Listed in the Genetic Testing Registry

Scientific Articles on PubMed

Catalog of Genes and Diseases from OMIM

Research Resources

References

  • Beall CM, Cavalleri GL, Deng L, Elston RC, Gao Y, Knight J, Li C, Li JC, Liang Y, McCormack M, Montgomery HE, Pan H, Robbins PA, Shianna KV, Tam SC, Tsering N, Veeramah KR, Wang W, Wangdui P, Weale ME, Xu Y, Xu Z, Yang L, Zaman MJ, Zeng C, Zhang L, Zhang X, Zhaxi P, Zheng YT. Natural selection on EPAS1 (HIF2alpha) associated with low hemoglobin concentration in Tibetan highlanders. Proc Natl Acad Sci U S A. 2010 Jun 22;107(25):11459-64. doi: 10.1073/pnas.1002443107. Epub 2010 Jun 7. Citation on PubMed or Free article on PubMed Central
  • Furlow PW, Percy MJ, Sutherland S, Bierl C, McMullin MF, Master SR, Lappin TR, Lee FS. Erythrocytosis-associated HIF-2alpha mutations demonstrate a critical role for residues C-terminal to the hydroxylacceptor proline. J Biol Chem. 2009 Apr 3;284(14):9050-8. doi: 10.1074/jbc.M808737200. Epub 2009 Feb 10. Citation on PubMed or Free article on PubMed Central
  • Lee FS, Percy MJ. The HIF pathway and erythrocytosis. Annu Rev Pathol. 2011;6:165-92. doi: 10.1146/annurev-pathol-011110-130321. Review. Citation on PubMed
  • McMullin MF. HIF pathway mutations and erythrocytosis. Expert Rev Hematol. 2010 Feb;3(1):93-101. doi: 10.1586/ehm.09.68. Review. Citation on PubMed
  • Percy MJ, Chung YJ, Harrison C, Mercieca J, Hoffbrand AV, Dinardo CL, Santos PC, Fonseca GH, Gualandro SF, Pereira AC, Lappin TR, McMullin MF, Lee FS. Two new mutations in the HIF2A gene associated with erythrocytosis. Am J Hematol. 2012 Apr;87(4):439-42. doi: 10.1002/ajh.23123. Epub 2012 Feb 24. Citation on PubMed or Free article on PubMed Central
  • Percy MJ, Rumi E. Genetic origins and clinical phenotype of familial and acquired erythrocytosis and thrombocytosis. Am J Hematol. 2009 Jan;84(1):46-54. doi: 10.1002/ajh.21313. Review. Citation on PubMed
  • Percy MJ. Familial erythrocytosis arising from a gain-of-function mutation in the HIF2A gene of the oxygen sensing pathway. Ulster Med J. 2008 May;77(2):86-8. Review. Citation on PubMed or Free article on PubMed Central
  • Perrotta S, Della Ragione F. The HIF2A gene in familial erythrocytosis. N Engl J Med. 2008 May 1;358(18):1966; author reply 1966-7. Citation on PubMed
  • Simonson TS, McClain DA, Jorde LB, Prchal JT. Genetic determinants of Tibetan high-altitude adaptation. Hum Genet. 2012 Apr;131(4):527-33. doi: 10.1007/s00439-011-1109-3. Epub 2011 Nov 9. Review. Citation on PubMed
  • van Wijk R, Sutherland S, Van Wesel AC, Huizinga EG, Percy MJ, Bierings M, Lee FS. Erythrocytosis associated with a novel missense mutation in the HIF2A gene. Haematologica. 2010 May;95(5):829-32. doi: 10.3324/haematol.2009.017582. Epub 2009 Dec 8. Citation on PubMed or Free article on PubMed Central
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