Endothelial PAS domain-containing protein 1 (EPAS1, also known as hypoxia-inducible factor-2alpha (HIF-2α)) is aprotein that is encoded by theEPAS1gene in mammals. It is a type ofhypoxia-inducible factor, a group oftranscription factors involved in the physiological response to oxygen concentration.[5][6][7][8] The gene is active underhypoxic conditions. It is also important in the development of the heart, and for maintaining thecatecholamine balance required for protection of the heart. Mutation often leads toneuroendocrine tumors.
However, several characterizedalleles ofEPAS1 contribute tohigh-altitude adaptation in humans.[9][10] One such allele, which has been inherited fromDenisovanarchaic hominins, is known to confer increased athletic performance in some people, and has therefore been referred to as the "super athlete gene".[11]
The EPAS1 gene encodes one subunit of atranscription factor involved in the induction of genes regulated by oxygen, and which is induced as oxygen concentration falls (hypoxia). The protein contains abasic helix-loop-helix protein dimerization domain as well as a domain found insignal transduction proteins which respond to oxygen levels. EPAS1 is involved in the development of theembryonic heart and is expressed inendothelial cells that line the walls ofblood vessels in theumbilical cord.
EPAS1 is also essential for the maintenance ofcatecholamine homeostasis and protection againstheart failure during early embryonic development.[8]Catecholamines regulated by EPAS1 includeepinephrine andnorepinephrine. It is critical that the production of catecholamines remain inhomeostatic conditions so that both the delicatefetal heart and the adult heart do not overexert themselves and induce heart failure. Catecholamine production in the embryo is related to control ofcardiac output by increasing thefetal heart rate.[12]
A high percentage ofTibetans carry an allele of EPAS1 that improves oxygen transport. The beneficial allele is also found in the extinctDenisovan genome, suggesting that it arose in them and entered the modern human population throughhybridization.[13]
TheHimalayan wolf[14] and theTibetan mastiff[15] have inherited an altitude-adaptive allele of the gene from interbreeding with aghost population of an unknown wolf-like canid. The EPAS1 allele is known to confer an adaptive advantage to animals living at high-altitudes.[14]
Mutations in the EPAS1 gene are related to early-onset neuroendocrine tumors such asparagangliomas,somatostatinomas and/orpheochromocytomas. The mutations are commonlysomaticmissense mutations that locate in the primary hydroxylation site of HIF-2α, which disrupt the protein hydroxylation/degradation mechanism, and leads to protein stabilization and pseudohypoxic signaling. In addition, these neuroendocrine tumors releaseerythropoietin (EPO) into circulating blood, and lead topolycythemia.[16][17]
Mutations in this gene are associated witherythrocytosis familial type 4,[8]pulmonary hypertension, andchronic mountain sickness.[18] There is also evidence that certain variants of this gene provide protection for people living at high altitude such as in Tibet.[9][10][19] The effect is most profound among the Tibetans living in the Himalayas at an altitude of about 4,000 metres above sea level, the environment of which is intolerable to other human populations due to 40% less atmospheric oxygen.
A study byUC Berkeley identified more than 30 genetic factors that make Tibetans' bodies well-suited for high-altitudes, including EPAS1.[20] Tibetans suffer no health problems associated withaltitude sickness, but instead produce low levels of blood pigment (haemoglobin) sufficient for less oxygen, more elaborate blood vessels,[21] have lower infant mortality,[22] and are heavier at birth.[23]
EPAS1 is useful in high altitudes as a short term adaptive response. However, EPAS1 can also cause excessive production of red blood cells leading to chronic mountain sickness that can lead to death and inhibited reproductive abilities. Some mutations that increase its expression are associated with increased hypertension and stroke at low altitude, with symptoms similar to mountain sickness. Populations living permanently at high altitudes experience selection on EPAS1 for mutations which reduce the negative fitness consequences of excessive red blood cell production.[19]
Belzutifan is a HIF-2α inhibitor, a medication approved in United States, United Kingdom, and European Union.
Takahata S, Sogawa K, Kobayashi A, Ema M, Mimura J, Ozaki N, et al. (July 1998). "Transcriptionally active heterodimer formation of an Arnt-like PAS protein, Arnt3, with HIF-1a, HLF, and clock".Biochemical and Biophysical Research Communications.248 (3):789–94.Bibcode:1998BBRC..248..789T.doi:10.1006/bbrc.1998.9012.PMID9704006.
Luo JC, Shibuya M (March 2001). "A variant of nuclear localization signal of bipartite-type is required for the nuclear translocation of hypoxia inducible factors (1alpha, 2alpha and 3alpha)".Oncogene.20 (12):1435–44.doi:10.1038/sj.onc.1204228.PMID11313887.S2CID40330235.
Mole DR, Pugh CW, Ratcliffe PJ, Maxwell PH (2002). "Regulation of the HIF pathway: enzymatic hydroxylation of a conserved prolyl residue in hypoxia-inducible factor alpha subunits governs capture by the pVHL E3 ubiquitin ligase complex".Advances in Enzyme Regulation.42:333–47.doi:10.1016/S0065-2571(01)00037-1.PMID12123724.
