Familial erythrocytosis is an inherited condition characterized by an increased number of red blood cells (erythrocytes). The primary function of these cells is to carry oxygen from the lungs to tissues and organs throughout the body. Signs and symptoms of familial erythrocytosis can include headaches, dizziness, nosebleeds, and shortness of breath. The excess red blood cells also increase the risk of developing abnormal blood clots that can block the flow of blood through arteries and veins. If these clots restrict blood flow to essential organs and tissues (particularly the heart, lungs, or brain), they can cause life-threatening complications such as a heart attack or stroke. However, many people with familial erythrocytosis experience only mild signs and symptoms or never have any problems related to their extra red blood cells.

Familial erythrocytosis can result from mutations in the EPOR, VHL, EGLN1, or EPAS1 gene. Researchers define four types of familial erythrocytosis, ECYT1 through ECYT4, based on which of these genes is altered.

The EPOR gene provides instructions for making a protein known as the erythropoietin receptor, which is found on the surface of certain blood-forming cells in the bone marrow. Erythropoietin is a hormone that directs the production of new red blood cells. Erythropoietin fits into the receptor like a key into a lock, triggering signaling pathways that lead to the formation of red blood cells. Mutations in the EPOR gene cause the erythropoietin receptor to be turned on for an abnormally long time after attaching to erythropoietin. The overactive receptor signals the production of red blood cells even when they are not needed, which results in an excess of these cells in the bloodstream. When familial erythrocytosis is caused by mutations in the EPOR gene, it is known as ECYT1.

The proteins produced from the VHL, EGLN1, and EPAS1 genes are also involved in red blood cell production; they each play a role in regulating erythropoietin. The protein produced from the EPAS1 gene is one component of a protein complex called hypoxia-inducible factor (HIF). When oxygen levels are lower than normal (hypoxia), HIF activates genes that help the body adapt, including the gene that provides instructions for making erythropoietin. Erythropoietin stimulates the production of more red blood cells to carry oxygen to organs and tissues. The proteins produced from the VHL and EGLN1 genes indirectly regulate erythropoietin by controlling the amount of available HIF. Mutations in any of these three genes can disrupt the regulation of red blood cell formation, leading to an overproduction of these cells. When familial erythrocytosis results from VHL gene mutations it is known as ECYT2; when the condition is caused by EGLN1 gene mutations it is called ECYT3; and when the condition results from EPAS1 gene mutations it is known as ECYT4.

Researchers have also described non-familial (acquired) forms of erythrocytosis. Causes of acquired erythrocytosis include long-term exposure to high altitude, chronic lung or heart disease, episodes in which breathing slows or stops for short periods during sleep (sleep apnea), and certain types of tumors. Another form of acquired erythrocytosis, called polycythemia vera, results from somatic (non-inherited) mutations in other genes involved in red blood cell production. In some cases, the cause of erythrocytosis is unknown.

Normal Function

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

Familial erythrocytosis

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.

Other Names for This Gene

• ECYT3
• egl nine homolog 1
• egl nine homolog 1 (C. elegans)
• egl nine-like protein 1
• egl-9 family hypoxia-inducible factor 1
• EGLN1_HUMAN
• HIF prolyl hydroxylase 2
• HIF-PH2
• HIF-prolyl hydroxylase 2
• HIFPH2
• HPH-2
• HPH2
• hypoxia-inducible factor prolyl hydroxylase 2
• PHD2
• prolyl hydroxylase domain-containing protein 2
• zinc finger MYND domain-containing protein 6
• ZMYND6

Genomic Location

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.

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

Genomic Location

Normal Function

The EPOR gene provides instructions for making a protein called the erythropoietin receptor. Erythropoietin is a hormone that directs the production of new red blood cells (erythrocytes) in the bone marrow. Red blood cells make up about half of total blood volume, and their primary function is to carry oxygen from the lungs to tissues and organs throughout the body. New red blood cells are constantly being produced by the body as worn-out red blood cells are broken down. To trigger the production of red blood cells, erythropoietin attaches (binds) to the erythropoietin receptor. This binding turns on (activates) the receptor, which stimulates several signaling pathways (particularly a cascade of signals known as the JAK/STAT pathway) that lead to the formation and maturation of red blood cells.

Health Conditions Related to Genetic Changes

Familial erythrocytosis

At least 16 mutations in the EPOR 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 EPOR gene mutations, it is often designated ECYT1.

Most of the identified mutations in the EPOR gene lead to the production of an abnormally short version of the erythropoietin receptor. A few mutations change single protein building blocks (amino acids) in the receptor. All of these mutations alter the structure of the receptor, causing it to remain activated for an abnormally long time after binding to erythropoietin. The overactive receptor signals the production of red blood cells even when no more are needed, which leads to an excess of these cells in the bloodstream.

Other Names for This Gene

• EPO-R
• EPOR_HUMAN

Genomic Location

Normal Function

The VHL gene provides instructions for making a protein that functions as part of a complex (a group of proteins that work together) called the VCB-CUL2 complex. This complex targets other proteins to be broken down (degraded) by the cell when they are no longer needed. Protein degradation is a normal process that removes damaged or unnecessary proteins and helps maintain the normal functions of cells.

One of the targets of the VCB-CUL2 complex is a protein called hypoxia-inducible factor 2-alpha (HIF-2α). HIF-2α 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 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's function is particularly important when oxygen levels are lower than normal (hypoxia). However, when adequate oxygen is available, the VCB-CUL2 complex keeps HIF from building up inappropriately in cells.

The VHL protein likely plays a role in other cellular functions, including the regulation of other genes and control of cell division. Based on this function, the VHL protein is classified as a tumor suppressor, which means it prevents cells from growing and dividing too rapidly or in an uncontrolled way. The VHL protein is also involved in the formation of the extracellular matrix, which is an intricate lattice that forms in the spaces between cells and provides structural support to tissues.

Health Conditions Related to Genetic Changes

Nonsyndromic paraganglioma

Mutations in the VHL gene increase the risk of developing tumors of the nervous system called paragangliomas or pheochromocytomas (a type of paraganglioma). Pheochromocytomas are a feature of von Hippel-Lindau syndrome, but they and other paragangliomas can also occur nonsyndromically (without the other signs and symptoms of the syndrome).

VHL gene mutations associated with nonsyndromic paraganglioma or pheochromocytoma can be inherited or can occur spontaneously. Some spontaneous mutations associated with this condition occur during the formation of reproductive cells (eggs or sperm) or just after fertilization and are called de novo mutations. This type of mutation is found in every cell of the body. Other spontaneous mutations found in this condition, called somatic mutations, are acquired during a person's lifetime and are present only in the tumor cells.

The VHL gene mutations found in nonsyndromic paraganglioma or pheochromocytoma change single amino acids in the VHL protein or create an abnormally short protein. These changes disrupt the function of the protein. As in von Hippel-Lindau syndrome, when the VHL protein is altered, the HIF-2α protein is not broken down, and instead builds up in cells. Excess HIF stimulates cells to divide abnormally and triggers the production of blood vessels when they are not needed, which can lead to the development of paraganglioma or pheochromocytoma.

Familial erythrocytosis

At least 10 inherited mutations in the VHL gene have been found to cause familial erythrocytosis, a condition characterized by an increased number of red blood cells and an elevated risk of abnormal blood clots. When familial erythrocytosis results from VHL gene mutations, it is often designated ECYT2.

The first VHL gene mutation related to familial erythrocytosis was identified in the Chuvash population of Russia. (It has since been found in other geographic regions as well.) The mutation changes a single protein building block (amino acid) in the VHL protein, replacing the amino acid arginine with the amino acid tryptophan at position 200 (written as Arg200Trp or R200W). This mutation disrupts the function of the VHL protein, particularly its ability to target HIF-2α to be broken down. As a result, 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, which leads to an excess of these cells in the bloodstream.

The other VHL gene mutations that can cause familial erythrocytosis also change single amino acids in the VHL protein. These genetic changes are thought to have similar effects on protein function to those of the Arg200Trp mutation. These mutations have been identified in the Chuvash population and in other regions worldwide.

Von Hippel-Lindau syndrome

More than 370 inherited mutations in the VHL gene have been identified in people with von Hippel-Lindau syndrome, a disorder characterized by the formation of tumors and fluid-filled sacs (cysts) in many different parts of the body. VHL gene mutations associated with this condition either prevent the production of any VHL protein or lead to the production of an abnormal version of the protein.

When the VHL protein is altered or missing, the VCB-CUL2 complex cannot target HIF-2α and other proteins to be broken down. As a result, HIF can build up in cells. Excess HIF stimulates cells to divide abnormally and triggers the production of blood vessels when they are not needed. Rapid and uncontrolled cell division, along with the abnormal formation of new blood vessels, can lead to the development of cysts and tumors in people with von Hippel-Lindau syndrome.

Other disorders

Mutations in the VHL gene have been identified in a type of tumor called a hemangioblastoma. These tumors are made of newly formed blood vessels and tend to develop in the brain and spinal cord. Hemangioblastomas are a characteristic feature of von Hippel-Lindau syndrome, but they can also occur sporadically (without the other signs and symptoms of that condition). When these tumors develop in people without von Hippel-Lindau syndrome, they are associated with somatic mutations in the VHL gene. The somatic mutations associated with hemangioblastomas are acquired during a person's lifetime and are present only in the cells that give rise to blood and blood vessels.

It is unclear how inherited and somatic mutations in the VHL gene are associated with such a wide variety of different conditions.

Cancers

Somatic (noninherited) mutations in the VHL gene are associated with a form of kidney cancer called clear cell renal cell carcinoma. This type of cancer is described as sporadic when it develops in people without inherited VHL mutations.

Instead of occurring in every cell in the body, somatic VHL mutations occur only in certain kidney cells. These genetic changes prevent the cells from producing functional VHL protein. A lack of this protein allows the cells to grow and divide abnormally, which may contribute to the development of sporadic kidney tumors. In addition, somatic mutations in the VHL gene in kidney cells may promote the growth of existing kidney tumors.

Other Names for This Gene

• pVHL
• VHL1
• VHL_HUMAN

Genomic Location

Familial erythrocytosis can have different inheritance patterns depending on the gene involved.

When the condition is caused by mutations in the EPOR, EGLN1, or EPAS1 gene, it has an autosomal dominant pattern of inheritance. Autosomal dominant inheritance means one copy of the altered gene in each cell is sufficient to cause the disorder. Most affected individuals inherit the altered gene from one affected parent.

When familial erythrocytosis is caused by mutations in the VHL gene, it has an autosomal recessive pattern of inheritance. Autosomal recessive inheritance means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

Familial erythrocytosis is a rare condition; its prevalence is unknown.