EPAS1

Endothelial PAS domain-containing protein 1 (EPAS1, also known as Hypoxia-inducible factor-2alpha (HIF-2alpha)) is a is_associated_with::protein that in humans is encoded by the EPAS1 is_associated_with::gene. It is a type of is_associated_with::hypoxia-inducible factors, a group of is_associated_with::transcription factors involved in body response to oxygen level. The gene is active under low oxygen condition called hypoxia. It is also important in the development of heart, and maintaining is_associated_with::catecholamine balance required for protection of the heart. Mutation often leads to neuroendocrine tumors.

However, a special version (allele) of EPAS1 produces EPAS1 which is responsible for is_associated_with::high-altitude adaptation in humans. It is known that the variant gene confers increased athletic performance in some people, and hence, is dubbed the "super athlete gene".

Function
The EPAS1 gene encodes a half of a is_associated_with::transcription factor involved in the induction of genes regulated by oxygen, which is induced as oxygen levels fall (hypoxia). The encoded protein contains a is_associated_with::basic helix-loop-helix domain protein dimerization domain as well as a domain found in proteins in signal transduction pathways which respond to oxygen levels. EPAS 1 is involved in the development of the is_associated_with::embryonic heart and is expressed in the endothelial cells that line the walls of the blood vessels in the umbilical cord. It is essential in maintaining is_associated_with::catecholamine homeostasis and protection against heart failure during early embryonic development.

Catecholamines include is_associated_with::epinephrine and is_associated_with::norepinephrine. It is important for the production of catecholamines to remain in homeostatic conditions so that both the delicate fetal heart and the adult heart do not overexert themselves and induce heart failure. Catecholamine production in the embryo is related to control of cardiac output by increasing the fetal heart rate.

Alleles
Tibetans carry a high proportion of an allele that improves oxygen transport. The beneficial allele is also found in the extinct is_associated_with::Denisovan genome, suggesting that it arose in them and entered the modern human population by hybridization.

Clinical significance
Mutations in EPAS1 gene are related to early onset of neuroendocrine tumors such as paragangliomas, somatostatinomas and/or pheochromocytomas. The mutations are commonly somatic missense 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 release erythropoietin (EPO) into circulating blood, and lead to polycythemia.

Mutations in this gene are associated with erythrocytosis familial type 4, is_associated_with::pulmonary hypertension and chronic mountain sickness. There is also evidence that certain variants of this gene provide protection for people living at high altitude such as in Tibet. 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 of atmospheric oxygen. The Tibetans suffer no health problems associated with is_associated_with::altitude sickness, but instead produce low level of blood pigment (is_associated_with::haemoglobin) sufficient for less oxygen, more elaborate blood vessels, and exhibit extraordinary high birth weight.

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. People permanently living at high altitudes might experience selection of EPAS1 to reduce the fitness consequences of excessive red blood cell production.

Interactions
EPAS1 has been shown to interact with is_associated_with::Aryl hydrocarbon receptor nuclear translocator and is_associated_with::ARNTL.