The EGLN1 gene, often known as PHD2, provides instructions for making an enzyme called prolyl hydroxylase domain 2 (PHD2). The PHD2 enzyme interacts with a protein called hypoxia-inducible factor 2-alpha (HIF-2α). This protein is one part (subunit) of a larger HIF protein complex that 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.
The PHD2 enzyme's primary job is to target HIF-2α to be broken down (degraded) so it does not build up when it is not needed. When enough oxygen is available, the PHD2 enzyme is highly active to stimulate the breakdown of HIF-2α. However, when oxygen levels are lower than normal (hypoxia), the PHD2 enzyme becomes less active. As a result, HIF-2α is degraded more slowly, leaving more HIF available to stimulate the formation of new blood vessels and 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 EGLN1 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.
Researchers suspect that the EGLN1 gene may also act as a tumor suppressor gene because of its role in regulating cell division and other processes through its interaction with HIF. Tumor suppressors prevent cells from growing and dividing too fast or in an uncontrolled way, which could lead to the development of a tumor.
Health Conditions Related to Genetic Changes
At least 10 mutations in the EGLN1 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 EGLN1 gene mutations, it is often designated ECYT3.
Some EGLN1 gene mutations change single protein building blocks (amino acids) in the PHD2 enzyme, while others lead to the production of an abnormally short version of the enzyme. Any of these genetic changes disrupt the enzyme's ability to interact with HIF-2α and target it for destruction. Consequently, 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.
At least one of the known EGLN1 gene mutations has been associated with both familial erythrocytosis and a tumor called a paraganglioma in the same individual. Paragangliomas are noncancerous (benign) tumors of the nervous system. The mutation, written as His374Arg or H374R, replaces the amino acid histidine with the amino acid arginine at position 374 in the PHD2 enzyme. This genetic change alters the interaction between the PHD2 enzyme and HIF-2α, which leads to the production of excess red blood cells. However, it is unclear how the mutation may be associated with the development of paragangliomas.More About This Health Condition
Other Names for This Gene
- egl nine homolog 1
- egl nine homolog 1 (C. elegans)
- egl nine-like protein 1
- egl-9 family hypoxia-inducible factor 1
- HIF prolyl hydroxylase 2
- HIF-prolyl hydroxylase 2
- hypoxia-inducible factor prolyl hydroxylase 2
- prolyl hydroxylase domain-containing protein 2
- zinc finger MYND domain-containing protein 6
Additional Information & Resources
Tests Listed in the Genetic Testing Registry
Scientific Articles on PubMed
Catalog of Genes and Diseases from OMIM
- Al-Sheikh M, Moradkhani K, Lopez M, Wajcman H, Prehu C. Disturbance in the HIF-1alpha pathway associated with erythrocytosis: further evidences brought by frameshift and nonsense mutations in the prolyl hydroxylase domain protein 2 (PHD2) gene. Blood Cells Mol Dis. 2008 Mar-Apr;40(2):160-5. doi: 10.1016/j.bcmd.2007.07.017. Epub 2007 Oct 15. Citation on PubMed
- Albiero E, Ruggeri M, Fortuna S, Finotto S, Bernardi M, Madeo D, Rodeghiero F. Isolated erythrocytosis: study of 67 patients and identification of three novel germ-line mutations in the prolyl hydroxylase domain protein 2 (PHD2) gene. Haematologica. 2012 Jan;97(1):123-7. doi: 10.3324/haematol.2010.039545. Epub 2011 Aug 9. Citation on PubMed or Free article on PubMed Central
- Ladroue C, Carcenac R, Leporrier M, Gad S, Le Hello C, Galateau-Salle F, Feunteun J, Pouyssegur J, Richard S, Gardie B. PHD2 mutation and congenital erythrocytosis with paraganglioma. N Engl J Med. 2008 Dec 18;359(25):2685-92. doi: 10.1056/NEJMoa0806277. Citation on PubMed
- Ladroue C, Hoogewijs D, Gad S, Carcenac R, Storti F, Barrois M, Gimenez-Roqueplo AP, Leporrier M, Casadevall N, Hermine O, Kiladjian JJ, Baruchel A, Fakhoury F, Bressac-de Paillerets B, Feunteun J, Mazure N, Pouyssegur J, Wenger RH, Richard S, Gardie B. Distinct deregulation of the hypoxia inducible factor by PHD2 mutants identified in germline DNA of patients with polycythemia. Haematologica. 2012 Jan;97(1):9-14. doi: 10.3324/haematol.2011.044644. Epub 2011 Sep 20. 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. 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. Citation on PubMed
- Percy MJ, Furlow PW, Beer PA, Lappin TR, McMullin MF, Lee FS. A novel erythrocytosis-associated PHD2 mutation suggests the location of a HIF binding groove. Blood. 2007 Sep 15;110(6):2193-6. doi: 10.1182/blood-2007-04-084434. Epub 2007 Jun 19. 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. Citation on PubMed
- Percy MJ, Zhao Q, Flores A, Harrison C, Lappin TR, Maxwell PH, McMullin MF, Lee FS. A family with erythrocytosis establishes a role for prolyl hydroxylase domain protein 2 in oxygen homeostasis. Proc Natl Acad Sci U S A. 2006 Jan 17;103(3):654-9. doi: 10.1073/pnas.0508423103. Epub 2006 Jan 9. Citation on PubMed or Free article on PubMed Central
- 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. Citation on PubMed
- Simonson TS, Yang Y, Huff CD, Yun H, Qin G, Witherspoon DJ, Bai Z, Lorenzo FR, Xing J, Jorde LB, Prchal JT, Ge R. Genetic evidence for high-altitude adaptation in Tibet. Science. 2010 Jul 2;329(5987):72-5. doi: 10.1126/science.1189406. Epub 2010 May 13. Citation on PubMed