Prostate cancer is a common disease that affects men, usually in middle age or later. In this disorder, certain cells in the prostate become abnormal, multiply without control or order, and form a tumor. The prostate is a gland that surrounds the male urethra and helps produce semen, the fluid that carries sperm.

Early prostate cancer usually does not cause pain, and most affected men exhibit no noticeable symptoms. Men are often diagnosed as the result of health screenings, such as a blood test for a substance called prostate specific antigen (PSA) or a medical exam called a digital rectal exam (DRE). As the tumor grows larger, signs and symptoms can include difficulty starting or stopping the flow of urine, a feeling of not being able to empty the bladder completely, blood in the urine or semen, or pain with ejaculation. However, these changes can also occur with many other genitourinary conditions. Having one or more of these symptoms does not necessarily mean that a man has prostate cancer.

The severity and outcome of prostate cancer varies widely. Early-stage prostate cancer can usually be treated successfully, and some older men have prostate tumors that grow so slowly that they may never cause health problems during their lifetime, even without treatment. In other men, however, the cancer is much more aggressive; in these cases, prostate cancer can be life-threatening.

Some cancerous tumors can invade surrounding tissue and spread to other parts of the body. Tumors that begin at one site and then spread to other areas of the body are called metastatic cancers. The signs and symptoms of metastatic cancer depend on where the disease has spread. If prostate cancer spreads, cancerous cells most often appear in the lymph nodes, bones, lungs, liver, or brain.

A small percentage of prostate cancers are hereditary and occur in families. These hereditary cancers are associated with inherited gene variants. Hereditary prostate cancers tend to develop earlier in life than non-inherited (sporadic) cases.

About 1 in 7 men will be diagnosed with prostate cancer at some time during their life. In addition, studies indicate that many older men have undiagnosed prostate cancer that is non-aggressive and unlikely to cause symptoms or affect their lifespan. While most men who are diagnosed with prostate cancer do not die from it, this common cancer is still the second leading cause of cancer death among men in the United States.

More than 60 percent of prostate cancers are diagnosed after age 65, and the disorder is rare before age 40. In the United States, African Americans have a higher risk of developing prostate cancer than do men of other ethnic backgrounds, and they also have a higher risk of dying from the disease.

Cancers occur when genetic variants (also known as mutations) build up in critical genes, specifically those that control cell growth and division or the repair of damaged DNA. These changes allow cells to grow and divide uncontrollably to form a tumor. In most cases of prostate cancer, these genetic changes are acquired during a man's lifetime and are present only in certain cells in the prostate. These changes, which are called somatic variants, are not inherited. Somatic variants in many different genes have been found in prostate cancer cells. Less commonly, genetic changes present in essentially all of the body's cells increase the risk of developing prostate cancer. These genetic changes, which are classified as germline variants, are usually inherited from a parent. In people with germline variants, changes in other genes, together with environmental and lifestyle factors, also influence whether a person will develop prostate cancer.

Inherited variants in particular genes, such as BRCA1, BRCA2, and HOXB13, account for some cases of hereditary prostate cancer. Men with variants in these genes have a high risk of developing prostate cancer and, in some cases, other cancers during their lifetimes. In addition, men with BRCA2 or HOXB13 gene variants may have a higher risk of developing life-threatening forms of prostate cancer.

The proteins produced from the BRCA1 and BRCA2 genes are involved in fixing damaged DNA, which helps to maintain the stability of a cell's genetic information. For this reason, the BRCA1 and BRCA2 proteins are considered to be tumor suppressors, which means that they help keep cells from growing and dividing too fast or in an uncontrolled way. Variants in these genes impair the cell's ability to fix damaged DNA, allowing potentially damaging variants to persist. As these defects accumulate, they can trigger cells to grow and divide uncontrollably and form a tumor.

The HOXB13 gene provides instructions for producing a protein that attaches (binds) to specific regions of DNA and regulates the activity of other genes. On the basis of this role, the protein produced from the HOXB13 gene is called a transcription factor. Like BRCA1 and BRCA2, the HOXB13 protein is thought to act as a tumor suppressor. HOXB13 gene variants may result in impairment of the protein's tumor suppressor function, resulting in the uncontrolled cell growth and division that can lead to prostate cancer.

Inherited variations in dozens of other genes have been studied as possible risk factors for prostate cancer. Some of these genes provide instructions for making proteins that interact with the proteins produced from the BRCA1, BRCA2, or HOXB13 genes. Others act as tumor suppressors through different pathways. Changes in these genes probably make only a small contribution to overall prostate cancer risk. However, researchers suspect that the combined influence of variations in many of these genes may significantly impact a person's risk of developing this form of cancer.

In many families, the genetic changes associated with hereditary prostate cancer are unknown. Identifying additional genetic risk factors for prostate cancer is an active area of medical research.

In addition to genetic changes, researchers have identified many personal and environmental factors that may contribute to a person's risk of developing prostate cancer. These factors include a high-fat diet that includes an excess of meat and dairy and not enough vegetables, a largely inactive (sedentary) lifestyle, obesity, excessive alcohol use, or exposure to certain toxic chemicals. A history of prostate cancer in closely related family members is also an important risk factor, particularly if the cancer occurred at an early age.

Many cases of prostate cancer are not related to inherited gene changes. These cancers are associated with somatic variants that occur only in certain cells in the prostate.

When prostate cancer is related to inherited gene changes, the way that cancer risk is inherited depends on the gene involved. For example, variants in the BRCA1, BRCA2, and HOXB13 genes are inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to increase a person's chance of developing cancer. In other cases, the inheritance of prostate cancer risk is unclear. It is important to note that people inherit an increased risk of cancer, not the disease itself. Not all people who inherit variants in these genes will develop cancer.

Normal Function

The BRCA1 gene provides instructions for making a protein that acts as a tumor suppressor. Tumor suppressor proteins help prevent cells from growing and dividing too rapidly or in an uncontrolled way.

The BRCA1 protein is involved in repairing damaged DNA. In the nucleus of many types of normal cells, the BRCA1 protein interacts with several other proteins to mend breaks in DNA. These breaks can be caused by natural and medical radiation or other environmental exposures, and they also occur when chromosomes exchange genetic material in preparation for cell division. By helping to repair DNA, the BRCA1 protein plays a critical role in maintaining the stability of a cell's genetic information.

Research suggests that the BRCA1 protein also regulates the activity of other genes and plays an essential role in embryonic development. To carry out these functions, the BRCA1 protein interacts with many other proteins, including other tumor suppressors and proteins that regulate cell division.

Health Conditions Related to Genetic Changes

Breast cancer

Mutations in the BRCA1 gene are associated with an increased risk of breast cancer in both men and women, as well as several other types of cancer. These mutations are present in every cell in the body and can be passed from one generation to the next. As a result, they are associated with cancers that cluster in families. However, not everyone who inherits a mutation in the BRCA1 gene will develop cancer. Other genetic, environmental, and lifestyle factors also contribute to a person's cancer risk.

Most BRCA1 gene mutations lead to the production of an abnormally short version of the BRCA1 protein or prevent any protein from being made from one copy of the gene. As a result, less of this protein is available to help repair damaged DNA or fix mutations that occur in other genes. As these defects accumulate, they can trigger cells to grow and divide uncontrollably to form a tumor.

Ovarian cancer

Many of the same BRCA1 gene mutations that increase the risk of breast cancer (described above) also increase the risk of ovarian cancer. Families with these mutations are often said to be affected by hereditary breast and ovarian cancer syndrome. Women with BRCA1 gene mutations have a 35 to 60 percent chance of developing ovarian cancer in their lifetimes, as compared with 1.6 percent in the general population.

Prostate cancer

Inherited BRCA1 gene mutations have been found to increase the risk of prostate cancer. These mutations likely reduce the BRCA1 protein's ability to repair DNA, allowing potentially damaging mutations to persist in various other genes. The accumulation of damaging mutations can lead to the out-of-control cell growth and division that can cause a tumor to develop. Men who carry a BRCA1 gene mutation may also be at increased risk for other cancers, including breast and pancreatic cancer.

Cholangiocarcinoma

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Other cancers

Inherited mutations in the BRCA1 gene also increase the risk of several other types of cancer, including pancreatic cancer and colon cancer. These mutations impair the ability of the BRCA1 protein to help repair damaged DNA. As defects accumulate in DNA, they can trigger cells to grow and divide without order to form a tumor. It is not clear why different individuals with BRCA1 mutations develop cancers in different organs. Environmental factors that affect specific organs may contribute to the development of cancers at particular sites.

Other Names for This Gene

• BRCA1 gene
• BRCA1_HUMAN
• BRCC1
• breast cancer 1
• breast cancer 1 gene
• breast cancer 1, early onset
• breast cancer 1, early onset gene
• breast cancer type 1 susceptibility gene
• breast cancer type 1 susceptibility protein
• IRIS
• PPP1R53
• PSCP
• RNF53

Genomic Location

Normal Function

The BRCA2 gene provides instructions for making a protein that acts as a tumor suppressor. Tumor suppressor proteins help prevent cells from growing and dividing too rapidly or in an uncontrolled way.

The BRCA2 protein is involved in repairing damaged DNA. In the nucleus of many types of normal cells, the BRCA2 protein interacts with several other proteins to mend breaks in DNA. These breaks can be caused by natural and medical radiation or other environmental exposures, and they also occur when chromosomes exchange genetic material in preparation for cell division. By helping to repair DNA, the BRCA2 protein plays a critical role in maintaining the stability of a cell's genetic information.

Researchers suspect that the BRCA2 protein has additional functions within cells. For example, the protein may help regulate cytokinesis, which is the step in cell division when the fluid surrounding the nucleus (the cytoplasm) divides to form two separate cells. Researchers are investigating the protein's other potential activities.

Health Conditions Related to Genetic Changes

Breast cancer

Mutations in the BRCA2 gene are associated with an increased risk of breast cancer in both men and women, as well as several other types of cancer. These mutations are present in every cell in the body and can be passed from one generation to the next. As a result, they are associated with cancers that cluster in families. However, not everyone who inherits a mutation in the BRCA2 gene will develop cancer. Other genetic, environmental, and lifestyle factors also contribute to a person's cancer risk.

Most BRCA2 gene mutations lead to the production of an abnormally small, nonfunctional version of the BRCA2 protein from one copy of the gene in each cell. As a result, less of this protein is available to help repair damaged DNA or fix mutations that occur in other genes. As these defects accumulate, they can trigger cells to grow and divide uncontrollably to form a tumor.

Ovarian cancer

Many of the same BRCA2 gene mutations that increase the risk of breast cancer (described above) also increase the risk of ovarian cancer. Families with these mutations are often said to be affected by hereditary breast and ovarian cancer syndrome. Women with BRCA2 gene mutations have an approximately 12 to 25 percent chance of developing ovarian cancer in their lifetimes, as compared with 1.6 percent in the general population.

Prostate cancer

Inherited BRCA2 gene mutations have been found to increase the risk of prostate cancer. Men with these mutations are also more likely to develop prostate cancer at an earlier age and may be at increased risk of having an aggressive form of the disease. They may also be at increased risk for other cancers.

BRCA2 gene mutations likely reduce the BRCA2 protein's ability to repair DNA, allowing potentially damaging mutations to persist in various other genes. The accumulation of damaging mutations can lead to the out-of-control cell growth and division that can result in development of a tumor.

Cholangiocarcinoma

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Fanconi anemia

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Other cancers

Inherited mutations in the BRCA2 gene also increase the risk of several other types of cancer, including pancreatic cancer and an aggressive form of skin cancer called melanoma. These mutations impair the ability of the BRCA2 protein to help repair damaged DNA. As defects accumulate in DNA, they can trigger cells to grow and divide without order to form a tumor. It is not clear why different individuals with BRCA2 mutations develop cancers in different organs. Environmental factors that affect specific organs may contribute to the development of cancers at particular sites.

Other Names for This Gene

• brca 2 gene
• BRCA2_HUMAN
• BRCC2
• breast cancer 2
• breast cancer 2 gene
• breast cancer 2, early onset
• breast cancer 2, early onset gene
• breast cancer type 2 susceptibility gene
• breast cancer type 2 susceptibility protein
• FACD
• FAD
• FAD1
• FANCB
• FANCD1

Genomic Location

Normal Function

The HOXB13 gene provides instructions for producing a protein that attaches (binds) to specific regions of DNA and regulates the activity of other genes. On the basis of this role, the protein produced from the HOXB13 gene is called a transcription factor. The HOXB13 protein is part of a large group of transcription factors called the homeobox protein family. The HOXB13 protein is thought to play a role in the development and maintenance of the skin. It also acts as a tumor suppressor, which means that it keeps cells from growing and dividing too fast or in an uncontrolled way.

The HOXB13 protein has a characteristic homeobox region called the homeodomain, which binds to DNA, and two other regions called MEIS interacting domains. The MEIS interacting domains are thought to help regulate the activity of the HOXB13 protein by controlling the binding of the homeodomain with DNA.

Health Conditions Related to Genetic Changes

Prostate cancer

At least two mutations in the HOXB13 gene have been associated with an increased risk of prostate cancer; the disease may also be more aggressive in affected men with a HOXB13 mutation. These mutations are present in every cell of the body and can be passed from one generation to the next. As a result, they are associated with cancers that cluster in families. However, not everyone who inherits a mutation in the HOXB13 gene will ultimately develop prostate cancer. Other genetic, environmental, and lifestyle factors also contribute to a person's cancer risk.

The HOXB13 gene mutations that are associated with prostate cancer alter the MEIS interacting domains of the HOXB13 protein. Researchers suggest that the changes may impair the ability of these domains to regulate the HOXB13 protein's interactions with DNA. As a result, the protein's tumor suppressor function is impaired, resulting in the uncontrolled cell proliferation that can lead to prostate cancer.

Other Names for This Gene

• homeobox protein Hox-B13
• HXB13_HUMAN
• PSGD

Genomic Location

Normal Function

The LRP2 gene provides instructions for making a protein called megalin, which functions as a receptor. Receptor proteins have specific sites into which certain other proteins, called ligands, fit like keys into locks. Together, ligands and their receptors trigger signals that affect cell development and function. Megalin has many ligands involved in various body processes, including the absorption of vitamins A and D, immune functioning, stress response, and the transport of fats in the bloodstream.

Megalin is embedded in the membrane of cells that line the surfaces and cavities of the body (epithelial cells). The receptor helps move its ligands from the cell surface into the cell (endocytosis), and is also involved in transporting the ligands of a related receptor called cubulin. Megalin is active in the development and function of many parts of the body, including the brain and spinal cord (central nervous system), eyes, ears, lungs, intestine, reproductive system, and the small tubes in the kidneys where urine is formed (renal tubules).

Health Conditions Related to Genetic Changes

Donnai-Barrow syndrome

At least twelve LRP2 gene mutations have been identified in people with Donnai-Barrow syndrome. These mutations are believed to result in the absence of functional megalin protein. The lack of functional megalin in the renal tubules causes megalin's various ligands to be excreted in the urine rather than being absorbed back into the bloodstream. The features of Donnai-Barrow syndrome are probably caused by the inability of megalin to help absorb these ligands, disruption of biochemical signaling pathways, or other effects of the nonfunctional megalin protein. However, it is unclear how these abnormalities result in the specific signs and symptoms of the disorder.

A condition previously classified as a separate disorder called facio-oculo-acoustico-renal (FOAR) syndrome has also been found to be caused by LRP2 gene mutations. FOAR syndrome is now considered to be the same disorder as Donnai-Barrow syndrome.

Coloboma

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Prostate cancer

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Other disorders

Certain LRP2 gene polymorphisms have also been associated with increased levels of low-density lipoproteins (LDLs) and cholesterol in the blood. LDLs are the primary carriers of cholesterol in the blood. Cholesterol is a waxy, fat-like substance that is produced in the body and obtained from foods that come from animals. Increased LDL levels may result in excess cholesterol circulating through the bloodstream and accumulating on the walls of the blood vessels, increasing a person's risk of cardiovascular disease.

LDLs are among megalin's ligands, and researchers believe that variations in megalin function resulting from LRP2 gene changes may influence LDL levels.

Cancers

Certain common genetic variations (polymorphisms) in the LRP2 gene may be associated with differences in the progression, recurrence, and severity of prostate cancer in affected men. Androgens, which are male sex hormones that contribute to the growth of cancerous (malignant) prostate tumors, are among megalin's ligands. A recent study suggests that prostate tumor cells may produce increased amounts of megalin and thereby absorb more androgens. LRP2 gene polymorphisms that increase the activity of megalin may encourage more aggressive tumor growth, while polymorphisms that decrease the activity of megalin may tend to slow tumor growth.

Other Names for This Gene

• calcium sensor protein
• DBS
• glycoprotein 330 (gp330)
• gp330
• Heymann nephritis antigen homolog
• low density lipoprotein receptor-related protein 2
• LRP2_HUMAN
• megalin

Genomic Location

Normal Function

The MED12 gene provides instructions for making a protein called mediator complex subunit 12. As its name suggests, this protein forms one part (subunit) of the mediator complex, which is a group of about 25 proteins that work together to regulate gene activity. The mediator complex physically links transcription factors, which are proteins that influence whether genes are turned on or off, with an enzyme called RNA polymerase II. Once transcription factors are attached, this enzyme initiates gene transcription, the process by which information stored in a gene's DNA is used to build proteins.

Researchers believe that the MED12 protein is involved in many aspects of early development, including the development of nerve cells (neurons) in the brain. The MED12 protein is part of several chemical signaling pathways within cells. These pathways help direct a broad range of cellular activities, such as cell growth, cell movement (migration), and the process by which cells mature to carry out specific functions (differentiation).

Health Conditions Related to Genetic Changes

FG syndrome

At least two mutations in the MED12 gene have been found to cause FG syndrome, which is characterized by intellectual disability, behavioral problems, and physical abnormalities including weak muscle tone (hypotonia) and obstruction of the anal opening (imperforate anus).

The mutations that cause FG syndrome each change a single protein building block (amino acid) in the MED12 protein. One mutation replaces the amino acid arginine with the amino acid tryptophan at protein position 961 (written as Arg961Trp or R961W). The other replaces the amino acid glycine with the amino acid glutamic acid at protein position 958 (written as Gly958Glu or G958E). These mutations alter the structure of the MED12 protein, which likely disrupts its ability to regulate gene activity during development. However, it is unclear how the genetic changes lead to intellectual disability and the other features of FG syndrome.

Lujan syndrome

At least one mutation in the MED12 gene causes Lujan syndrome, a disorder characterized by intellectual disability, behavioral problems, and physical features including tall stature and a long, narrow face. This mutation is different than the genetic changes associated with FG syndrome (described above); the Lujan syndrome mutation replaces the amino acid asparagine with the amino acid serine at position 1007 of the MED12 protein (written as Asn1007Ser or N1007S). The mutation alters the structure of the MED12 protein and likely disrupts its ability to regulate gene activity, but it is not known how these changes affect development and lead to the specific features of Lujan syndrome.

Ohdo syndrome, Maat-Kievit-Brunner type

At least three MED12 gene mutations have been found to cause the Maat-Kievit-Brunner type of Ohdo syndrome, which is a rare condition characterized by intellectual disability and distinctive facial features. The mutations that cause this disorder change single amino acids in the MED12 gene, although they are not the same genetic changes that cause FG syndrome or Lujan syndrome (described above). The mutations that result in the Maat-Kievit-Brunner type of Ohdo syndrome change the structure of the MED12 gene, impairing its ability to control gene activity. It is unclear how these changes lead to the particular cognitive and physical features of the disorder.

Prostate cancer

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Tumors

Some gene mutations are acquired during a person's lifetime and are present only in certain cells. These changes, which are known as somatic mutations, are not inherited. Somatic mutations in the MED12 gene have been found in several types of tumors, both noncancerous and cancerous.

Somatic MED12 gene mutations are present in most uterine leiomyomas, which are noncancerous growths also known as uterine fibroids. Uterine leiomyomas are common in adult women. These growths can cause pelvic pain and abnormal bleeding, and, in some cases, lead to an inability to have biological children (infertility). Somatic MED12 gene mutations have also been identified in some cancerous uterine tumors, including leiomyosarcomas and smooth muscle tumors of uncertain malignant potential (STUMP), and in some prostate and colorectal cancers.

Studies suggest that somatic MED12 gene mutations alter the function of the MED12 protein, which likely disrupts normal cell signaling and impairs regulation of cell growth and other cell functions. As a result, certain cells may become able to divide in an uncontrolled way, leading to the growth of a tumor.

Other Names for This Gene

• CAGH45
• HOPA
• KIAA0192
• MED12_HUMAN
• mediator of RNA polymerase II transcription, subunit 12 homolog
• OKS
• OPA-containing protein
• OPA1
• thyroid hormone receptor-associated protein, 230 kDa subunit
• TNRC11
• TRAP230

Genomic Location

Normal Function

The NBN gene provides instructions for making a protein called nibrin. This protein is involved in several critical cellular functions, including the repair of damaged DNA.

Nibrin interacts with two other proteins, produced from the MRE11A and RAD50 genes, as part of a larger protein complex. Nibrin regulates the activity of this complex by carrying the MRE11A and RAD50 proteins into the cell's nucleus and guiding them to sites of DNA damage. The proteins work together to mend broken strands of DNA. DNA can be damaged by agents such as toxic chemicals or radiation, and breaks in DNA strands also occur naturally when chromosomes exchange genetic material in preparation for cell division. Repairing DNA prevents cells from accumulating genetic damage that may cause them to die or to divide uncontrollably.

The MRE11A/RAD50/NBN complex interacts with the protein produced from the ATM gene, which plays an essential role in recognizing broken strands of DNA and coordinating their repair. The MRE11A/RAD50/NBN complex helps maintain the stability of a cell's genetic information through its roles in repairing damaged DNA and regulating cell division. Because these functions are critical for preventing the formation of cancerous tumors, nibrin is described as a tumor suppressor.

Health Conditions Related to Genetic Changes

Nijmegen breakage syndrome

At least 10 mutations in the NBN gene have been found to cause Nijmegen breakage syndrome, a condition characterized by slow growth, recurrent infections, and an increased risk of developing cancer. The NBN gene mutations that cause Nijmegen breakage syndrome typically lead to the production of an abnormally short version of the nibrin protein. The mutation found in most affected individuals, particularly in Slavic populations of Eastern Europe, deletes five DNA building blocks (nucleotides) from the NBN gene (written as 657_661del5). This mutation leads to the production of a shortened version of the nibrin protein called p70-nibrin. This shortened protein is not as effective as normal nibrin in responding to DNA damage, but p70-nibrin does appear to have some residual function.

When breaks in DNA are not repaired properly, genetic damage can accumulate. A buildup of errors in DNA can trigger cells to grow and divide abnormally, increasing the risk of cancer in people with Nijmegen breakage syndrome. Nibrin's role in regulating cell division and cell growth (proliferation) is thought to lead to the problems with the immune system that are seen in affected individuals. A lack of functional nibrin results in less immune cell proliferation. A decrease in the amount of immune cells that are produced leads to a malfunctioning immune system. It is unclear how mutations in the NBN gene cause the other features of Nijmegen breakage syndrome.

Breast cancer

Inherited mutations in the NBN gene, including the c.657_661del5 mutation described above, have also been associated with several other types of cancer. Studies in Eastern European populations reported that people with mutations in one copy of the NBN gene in each cell may be more likely to develop breast cancer than people who do not carry NBN mutations. Cells with a mutation in one copy of the NBN gene do not repair DNA as effectively as cells without these mutations. It is thought that DNA damage accumulates over time, which can trigger cells to grow and divide uncontrollably and increase the risk of developing cancer.

Ovarian cancer

Inherited mutations in the NBN gene, including the c.657_661del5 mutation described above, have also been associated with several other types of cancer. Studies in Eastern European populations reported that people with mutations in one copy of the NBN gene in each cell may be more likely to develop ovarian cancer than people who do not carry NBN mutations. Cells with a mutation in one copy of the NBN gene do not repair DNA as effectively as cells without these mutations. It is thought that DNA damage accumulates over time, which can trigger cells to grow and divide uncontrollably and increase the risk of developing cancer.

Prostate cancer

Inherited mutations in the NBN gene, including the c.657_661del5 mutation described above, have also been associated with several other types of cancer. Studies in Eastern European populations reported that people with mutations in one copy of the NBN gene in each cell may be more likely to develop prostate cancer than people who do not carry NBN mutations. Cells with a mutation in one copy of the NBN gene do not repair DNA as effectively as cells without these mutations. It is thought that DNA damage accumulates over time, which can trigger cells to grow and divide uncontrollably and increase the risk of developing cancer.

Other cancers

Inherited mutations in the NBN gene, including the c.657_661del5 mutation described above, have also been associated with several other types of cancer. Studies in Eastern European populations reported that people with mutations in one copy of the NBN gene in each cell may be more likely to develop an aggressive form of skin cancer (melanoma) or cancer of blood-forming cells (leukemia) than people who do not carry NBN mutations. Cells with a mutation in one copy of the NBN gene do not repair DNA as effectively as cells without these mutations. It is thought that DNA damage accumulates over time, which can trigger cells to grow and divide uncontrollably and increase the risk of developing cancer.

Other Names for This Gene

• AT-V1
• AT-V2
• ATV
• Cell cycle regulatory protein p95
• NBN_HUMAN
• NBS
• NBS1
• Nijmegen breakage syndrome 1
• p95 protein of the MRE11/RAD50 complex

Genomic Location

Normal Function

The PCNT gene provides instructions for making a protein called pericentrin. Within cells, this protein is located in structures called centrosomes. Centrosomes play a role in cell division and the assembly of microtubules. Microtubules are fibers that help cells maintain their shape, assist in the process of cell division, and are essential for the transport of materials within cells.

Pericentrin acts as an anchoring protein, securing proteins to the centrosome that are necessary for its function. Through its interactions with these proteins, pericentrin is involved in the regulation of the cell cycle, which is the cell's way of replicating itself in an organized, step-by-step fashion.

Health Conditions Related to Genetic Changes

Microcephalic osteodysplastic primordial dwarfism type II

At least 30 mutations in the PCNT gene have been found to cause microcephalic osteodysplastic primordial dwarfism type II (MOPDII). These mutations result in the production of an abnormally short, nonfunctional pericentrin protein that cannot anchor other proteins to the centrosome. As a result, centrosomes cannot properly assemble microtubules, leading to disruption of the cell cycle and cell division. Impaired cell division causes a reduction in cell production, while disruption of the cell cycle can lead to cell death. This overall reduction in the number of cells leads to short bones, microcephaly, and the other signs and symptoms of MOPDII.

Prostate cancer

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Cancers

Gene mutations can be acquired during a person's lifetime and are present only in certain cells. These mutations are called somatic mutations, and they are not inherited. Somatic mutations in the PCNT gene can cause an increase in production of the pericentrin protein. Increased levels of pericentrin have been found in solid tumors (including prostate tumors) as well as cancers of blood-forming cells (leukemia and lymphoma). More pericentrin within the centrosome leads to overactivation of the cell cycle and increased cell division. This abnormal cell growth and division can eventually lead to a cancerous tumor.

Other disorders

Certain common genetic variations (polymorphisms) in the PCNT gene have been associated with an increased risk of developing psychiatric disorders such as schizophrenia and depression in some individuals. Similarly, increased levels of pericentrin have been found in some individuals with bipolar disorder. It is unclear how changes in the PCNT gene or increased levels of pericentrin protein are related to these disorders. A large number of genetic and environmental factors, most of which remain unknown, likely determine the risk of developing these complex conditions.

Other Names for This Gene

• PCN
• PCNT2
• PCNT_HUMAN
• PCNTB
• pericentrin B
• pericentrin-2

Genomic Location

Normal Function

The PTEN gene provides instructions for making an enzyme that is found in almost all tissues in the body. The enzyme acts as a tumor suppressor, which means that it helps regulate cell division by keeping cells from growing and dividing (proliferating) too rapidly or in an uncontrolled way. To function, the PTEN enzyme attaches (binds) to another PTEN enzyme (dimerizes) then binds to the cell membrane. The PTEN enzyme modifies other proteins and fats (lipids) by removing phosphate groups, each of which consists of a cluster of oxygen and phosphorus atoms. Enzymes with this function are called phosphatases.

The PTEN enzyme is part of a chemical pathway that signals cells to stop dividing and triggers cells to self-destruct through a process called apoptosis. Evidence suggests that this enzyme also helps control cell movement (migration), the sticking (adhesion) of cells to surrounding tissues, and the formation of new blood vessels (angiogenesis). Additionally, it likely plays a role in maintaining the stability of a cell's genetic information. All of these functions help prevent uncontrolled cell proliferation that can lead to the formation of tumors.

Health Conditions Related to Genetic Changes

Bannayan-Riley-Ruvalcaba syndrome

More than 30 mutations in the PTEN gene have been found to cause Bannayan-Riley-Ruvalcaba syndrome. Common features of this condition include a large head size (macrocephaly), multiple noncancerous tumors and tumor-like growths called hamartomas, and dark freckles on the penis in males. Bannayan-Riley-Ruvalcaba syndrome is one of several related conditions that are often considered together as PTEN hamartoma tumor syndrome (described below).

Some of the mutations that cause Bannayan-Riley-Ruvalcaba syndrome change single DNA building blocks (base pairs) in the PTEN gene or insert or delete a small number of base pairs. Other mutations result in an abnormally short enzyme or reduce the amount of enzyme that is produced. In about 10 percent of cases, Bannayan-Riley-Ruvalcaba syndrome results from the deletion of a large amount of genetic material that includes part or all of the PTEN gene. All of these genetic changes prevent the PTEN enzyme from regulating cell proliferation effectively, which can lead to uncontrolled cell growth and the formation of hamartomas and other types of tumors. Research is needed to determine what role PTEN gene mutations play in causing macrocephaly and the other features of Bannayan-Riley-Ruvalcaba syndrome.

Breast cancer

Inherited mutations in the PTEN gene increase the risk of developing breast cancer. In many cases, this increased risk occurs as part of Cowden syndrome (described below). Inherited mutations in the PTEN gene are thought to account for only a small fraction of all breast cancer cases.

Noninherited (somatic) PTEN gene mutations occur in some breast cancers in women without a family history of the disease. Somatic mutations are not inherited and do not occur as part of a familial cancer syndrome. They are acquired during a person's lifetime and occur only in certain cells in the breast. These mutations impair the tumor suppressor function of the PTEN enzyme, allowing cells to grow and divide without control or order. This uncontrolled cell growth contributes to the formation of a cancerous tumor. Studies suggest that a loss of functional PTEN enzyme is also related to poor responsiveness to a drug called trastuzumab (Herceptin), which is used to treat breast cancer.

Cowden syndrome

Researchers have identified more than 300 mutations in the PTEN gene that can cause Cowden syndrome or a similar disorder called Cowden-like syndrome. These conditions are characterized by the growth of multiple hamartomas and an increased risk of developing certain cancers, particularly breast cancer (described above), thyroid cancer, and cancer of the uterine lining (endometrial cancer). Cowden syndrome and Cowden-like syndrome are considered to be part of PTEN hamartoma tumor syndrome (described below).

Mutations that cause Cowden syndrome and Cowden-like syndrome include changes in a small number of base pairs and, in some cases, deletions of a larger amount of genetic material from the PTEN gene. These mutations lead to the production of a PTEN enzyme that does not function properly or does not work at all. The altered enzyme is unable to restrain cell division or signal abnormal cells to die, which contributes to the development of hamartomas and cancerous tumors.

Autism spectrum disorder

PTEN gene mutations have been identified in several people who have both an unusually large head size and the characteristic features of autism spectrum disorder, which affects communication and social interaction. Many of these mutations change single protein building blocks (amino acids) in the PTEN enzyme or lead to the production of an abnormally short version of the enzyme. Researchers are studying how changes in the PTEN gene are related to the risk of developing autism spectrum disorder. Some of these mutations have also been reported in families with PTEN hamartoma tumor syndrome (described below), and it is unclear how these mutations can cause different disorders.

Prostate cancer

Studies suggest that somatic mutations in the PTEN gene may be the most frequent genetic changes in prostate cancer. Mutations in the PTEN gene reduce or eliminate the tumor suppressor function of the PTEN enzyme. The loss of this enzyme's function likely permits certain cells to divide uncontrollably, contributing to the growth of cancerous tumors. In some cases, the presence of PTEN gene mutations is associated with more advanced stages of tumor growth.

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Other disorders

Several related conditions caused by mutations in the PTEN gene, including Bannayan-Riley-Ruvalcaba syndrome and Cowden syndrome (described above), are often considered together as PTEN hamartoma tumor syndrome. The mutations that cause these conditions are present in cells throughout the body and are often inherited from a parent. Some of the mutations that cause PTEN hamartoma tumor syndrome lead to a defective version of the PTEN enzyme that cannot perform its function as a tumor suppressor. Other mutations prevent the PTEN gene from producing any enzyme at all. Without functional PTEN enzyme, cell division is not controlled effectively and damaged cells continue to divide inappropriately, leading to the development of hamartomas and other tumors.

In some published case reports, mutations in the PTEN gene have been associated with Proteus syndrome, a rare condition characterized by asymmetric overgrowth of the bones, skin, and other tissues. However, many researchers now believe that individuals with PTEN gene mutations and asymmetric overgrowth do not meet the strict guidelines for a clinical diagnosis of Proteus syndrome. Instead, these individuals have a condition that is considered part of PTEN hamartoma tumor syndrome. One name that has been proposed for the condition is segmental overgrowth, lipomatosis, arteriovenous malformations, and epidermal nevus (SOLAMEN) syndrome; another is type 2 segmental Cowden syndrome. However, some scientific articles still refer to PTEN-related Proteus syndrome.

Other cancers

Somatic mutations in the PTEN gene are among the most common genetic changes found in human cancers. The cancers associated with somatic mutations are not inherited and do not occur as part of a cancer syndrome. Somatic mutations in the PTEN gene have been reported in many types of cancer, and studies suggest that PTEN may be the most frequently mutated gene in endometrial cancer. PTEN gene mutations are also commonly found in brain tumors called glioblastomas and astrocytomas, and in an aggressive form of skin cancer called melanoma. Mutations in the PTEN gene reduce or eliminate the tumor suppressor function of the PTEN enzyme. The loss of this enzyme's function likely permits certain cells to divide uncontrollably, contributing to the growth of cancerous tumors. In some cases, the presence of PTEN gene mutations is associated with more advanced stages of tumor growth.

Other Names for This Gene

• MMAC1
• mutated in multiple advanced cancers 1
• phosphatase and tensin homolog (mutated in multiple advanced cancers 1)
• phosphatase and tensin homolog deleted on chromosome 10
• protein-tyrosine phosphatase PTEN
• PTEN-MMAC1 protein
• PTEN1
• PTEN_HUMAN
• TEP1
• TEP1 phosphatase

Genomic Location

Normal Function

The SRD5A2 gene provides instructions for making an enzyme called steroid 5-alpha reductase 2. This enzyme is involved in processing androgens, which are hormones that direct male sexual development. Specifically, the enzyme is responsible for a chemical reaction that converts the hormone testosterone to a more potent androgen, dihydrotestosterone (DHT), in male reproductive tissues.

Testosterone and DHT are essential for the normal development of male sex characteristics. Before birth, testosterone is responsible for the formation of internal male genitalia, including the tubes that collect sperm and carry it out of the testes (the epididymis and vas deferens) and glands that help produce semen (the seminal vesicles). DHT directs the development of the external genitalia, including the penis and scrotum, and the prostate gland. During puberty, these two hormones also play an important role in the development of male secondary sex characteristics such as the growth of facial and body hair, increased muscle mass, and deepening of the voice.

Health Conditions Related to Genetic Changes

5-alpha reductase deficiency

About 50 mutations in the SRD5A2 gene have been identified in people with 5-alpha reductase deficiency. Most of these mutations change single protein building blocks (amino acids) in steroid 5-alpha reductase 2. Some of these genetic changes render the enzyme completely inactive. Other mutations reduce but do not eliminate the enzyme's function.

As a result of SRD5A2 mutations, the body cannot effectively convert testosterone to DHT in reproductive tissues. A shortage of DHT disrupts the formation of external genitalia before birth. People with 5-alpha reductase deficiency are genetically male, with one X and one Y chromosome in each cell, but they may be born with external genitalia that look female-typical, or that are not clearly male or clearly female. Other affected infants have external genitalia that appear male-typical, but they often have an unusually small penis (micropenis) and the urethra opening on the underside of the penis (hypospadias).

During puberty, the testes produce more testosterone. Researchers believe that people with 5-alpha reductase deficiency develop secondary male sex characteristics in response to higher levels of this hormone. Some affected people also retain a small amount of 5-alpha reductase 2 activity, which may produce DHT and contribute to the development of secondary sex characteristics during puberty.

Prostate cancer

Certain normal variations (polymorphisms) in the SRD5A2 gene may be associated with prostate cancer. Two of these polymorphisms have been studied extensively. The most common variation replaces the amino acid valine with the amino acid leucine at position 89 in steroid 5-alpha reductase 2 (written as Val89Leu or V89L). The other variation replaces the amino acid alanine with the amino acid threonine at position 49 in the enzyme (written as Ala49Thr or A49T). Some studies have suggested that these variations are associated with an increased risk of developing prostate cancer or having a more aggressive form of the disease. Other studies, however, have not shown these associations. It remains unclear what role SRD5A2 polymorphisms play in prostate cancer risk.

Some gene mutations are acquired during a person's lifetime and are present only in certain cells. These changes, which are called somatic mutations, are not inherited. Studies have shown that somatic SRD5A2 mutations in prostate cancer cells may be associated with the progression of prostate cancer. These mutations may increase the activity of steroid 5-alpha reductase 2, which would raise the levels of DHT in prostate tissue. Research has shown that androgens such as DHT can stimulate prostate cancer growth.

Other disorders

In women, certain polymorphisms in the SRD5A2 gene may affect the risk of developing a condition called polycystic ovary syndrome (PCOS). PCOS is characterized by a hormonal imbalance that can lead to irregular menstruation, acne, excess body hair (hirsutism), and weight gain. Some genetic variations increase the activity of steroid 5-alpha reductase 2 in the ovaries, which could contribute to the signs and symptoms of this condition. Other variations, including the common polymorphism Val89Leu, reduce the activity of steroid 5-alpha reductase 2 and are associated with a reduced risk of developing PCOS.

Other Names for This Gene

• 3-oxo-5 alpha-steroid 4-dehydrogenase 2
• 5 alpha-SR2
• MGC138457
• S5A2_HUMAN
• SR type 2
• steroid 5-alpha-reductase 2
• steroid-5-alpha-reductase, alpha polypeptide 2 (3-oxo-5 alpha-steroid delta 4-dehydrogenase alpha 2)
• Type II 5-alpha reductase

Genomic Location

Normal Function

The STAT3 gene is part of a family known as the STAT genes. These genes provide instructions for making proteins that are part of essential chemical signaling pathways within cells. When STAT proteins are turned on (activated) by certain chemical signals, they move into the cell's nucleus and attach (bind) to particular areas of DNA. The STAT proteins bind to regulatory regions near genes, which allows the proteins to control whether these genes are turned on or off. STAT proteins are called transcription factors on the basis of this action.

Through its regulation of gene activity, the STAT3 protein is involved in many cellular functions. It helps control cell growth and division (proliferation), cell movement (migration), and the self-destruction of cells (apoptosis).

The STAT3 protein is active in tissues throughout the body. It plays an important role in the development and function of several body systems and is essential for life. In the immune system, the STAT3 protein transmits signals for the maturation of immune system cells, especially T cells and B cells. These cells help control the body's response to foreign invaders such as bacteria and fungi.

In addition, the protein is involved in the regulation of inflammation, which is one way the immune system responds to infection or injury, and it plays a role in cellular processes that promote allergic reactions.

In the skeletal system, the STAT3 protein is involved in the formation of specialized cells that build and break down bone tissue. These cells are necessary for the normal development and maintenance of bones.

Health Conditions Related to Genetic Changes

Autosomal dominant hyper-IgE syndrome

More than 100 germline mutations in the STAT3 gene have been identified in people with autosomal dominant hyper-IgE syndrome (AD-HIES), a disorder of the immune system that leads to recurrent skin and lung infections as well as abnormalities of the bones, teeth, and blood vessels. The condition is characterized by high levels of an immune system protein called immunoglobulin E (IgE), which is involved in allergic reactions. Most of the mutations involved in this condition change single amino acids in the STAT3 protein.

Changes in the STAT3 gene that cause AD-HIES alter the structure and function of the STAT3 protein, impairing its ability to control the activity of other genes. Most of these mutations have a dominant-negative effect, which means that the altered protein produced from one copy of the STAT3 gene interferes with the function of the normal protein produced from the other copy of the gene.

The lack of STAT3's signaling function disrupts the normal maturation of T cells (specifically a subset known as Th17 cells) and other immune system cells. The resulting immune system abnormalities make people with AD-HIES highly susceptible to infections, particularly bacterial and fungal infections affecting the lungs and skin.

A shortage of functioning STAT3 protein prevents cells from reacting to signals that trigger allergic reactions, which explains why people with AD-HIES do not have an increased risk of allergies, despite having high levels of IgE. It is unclear why levels of this protein are elevated in affected individuals.

The role of STAT3 protein in the formation and maintenance of bone tissue may help explain why STAT3 gene mutations lead to the skeletal and dental abnormalities characteristic of this condition, but it is unclear what causes blood vessel abnormalities in AD-HIES.

Autoimmune lymphoproliferative syndrome

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Autoimmune disorders

At least 20 STAT3 gene mutations have been found to cause an autoimmune disorder that affects many body systems. Autoimmune disorders are a group of immune system abnormalities in which the immune system malfunctions and attacks the body's own cells and tissues.

In people with these STAT3 gene mutations, autoimmunity typically begins in infancy or early childhood and involves more than one body system. In these individuals, signs and symptoms commonly result from immune system attacks on insulin-producing cells in the pancreas (type 1 diabetes), red blood cells (autoimmune hemolytic anemia), platelets (autoimmune thrombocytopenia), or tissues in the digestive tract (autoimmune enteropathy).

The mutations involved in these conditions are typically inherited and are found in every cell of the body (known as germline mutations). They change single protein building blocks (amino acids) in the STAT3 protein, resulting in an altered protein that is abnormally active. Due to this effect, the mutations are classified as "gain-of-function."

Normally, the STAT3 protein is switched on and off in response to signals that control cell growth and development. A continuously active version of this protein relays messages to the nucleus even in the absence of these chemical signals. Abnormal STAT3 activity prevents normal control of the immune system, leading to autoimmunity.

Cancers

STAT3 gene mutations are found in approximately one-third of cases of a blood cancer called large granular lymphocytic leukemia (LGL), which is characterized by the accumulation of white blood cells (lymphocytes) that are abnormally large and contain structures called granules.

Individuals with LGL may also have an autoimmune disorder, primarily rheumatoid arthritis or autoimmune hemolytic anemia, and other blood cell abnormalities, such as pure red cell aplasia. There are two forms of the condition, based on the type of white blood cell involved: T-cell large granular lymphocytic leukemia (T-LGL) and chronic lymphoproliferative disorders of NK cells (CLPD-NKs). Both forms have the same signs and symptoms.

Unlike mutations that cause the autoimmunity (described above), LGL-associated STAT3 gene mutations are not inherited and are found only in the abnormal lymphocytes. (Such mutations are known as somatic mutations.) The mutations involved in LGL are classified as "gain-of-function," leading to an overactive STAT3 protein.

Researchers believe that the overactive STAT3 protein instructs cells to continue growing and dividing, and prevents damaged cells from self-destructing (undergoing apoptosis). Excess STAT3 protein may contribute to the growth of cancers by allowing abnormal cells to grow and divide uncontrollably.

Other Names for This Gene

• acute-phase response factor
• APRF
• APRF Transcription Factor
• DNA-binding protein APRF
• FLJ20882
• hypothetical protein MGC16063
• IL6-Response Factor
• LIF(leukemia inhibitory factor)-Response Factor
• LIF-Response Factor
• signal transducer and activator of transcription 3 (acute-phase response factor)
• STAT3_HUMAN

Genomic Location

Normal Function

The TGFBR1 gene provides instructions for making a protein called transforming growth factor-beta (TGF-β) receptor type 1. This receptor transmits signals from the cell surface into the cell through a process called signal transduction. Through this type of signaling, the environment outside the cell affects activities inside the cell such as stimulation of cell growth and division.

To carry out its signaling function, TGF-β receptor type 1 spans the cell membrane, so that one end of the protein projects from the outer surface of the cell (the extracellular domain) and the other end remains inside the cell (the intracellular domain). A protein called TGF-β attaches (binds) to the extracellular domain of TGF-β receptor type 1, which turns on (activates) the receptor and allows it to bind to another receptor on the cell surface. These three proteins form a complex, which triggers signal transduction by activating other proteins in a signaling pathway called the TGF-β pathway.

Signals transmitted by the TGF-β receptor complex trigger various responses by the cell, including the growth and division (proliferation) of cells, the maturation of cells to carry out specific functions (differentiation), cell movement (motility), and controlled cell death (apoptosis). Because TGF-β receptor type 1 helps prevent cells from growing and dividing too rapidly or in an uncontrolled way, it can suppress the formation of tumors.

Health Conditions Related to Genetic Changes

Loeys-Dietz syndrome

More than 35 mutations in the TGFBR1 gene have been found to cause Loeys-Dietz syndrome type I. Loeys-Dietz syndrome affects connective tissue, which gives structure and support to blood vessels, the skeleton, and other parts of the body. This type of Loeys-Dietz syndrome is characterized by blood vessel abnormalities and skeletal deformities. The TGFBR1 gene mutations that cause Loeys-Dietz syndrome are present in one copy of the gene in each cell. Most of these mutations change single protein building blocks (amino acids) in TGF-β receptor type 1, resulting in a receptor with little or no function. Although the receptor has severely reduced function, TGF-β pathway signaling occurs at an even greater intensity than normal. Researchers speculate that the activity of other proteins in this signaling pathway is increased to compensate for the reduction in TGF-β receptor type 1 activity; however, the exact mechanism responsible for the increase in signaling is unclear. The overactive signaling pathway disrupts development of connective tissue and various body systems and leads to the varied signs and symptoms of Loeys-Dietz syndrome type I.

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Other cancers

More than 10 mutations in the TGFBR1 gene have been found to increase the risk of developing a form of skin cancer called multiple self-healing squamous epithelioma (MSSE). This condition, also known as Ferguson-Smith disease, is characterized by the formation of multiple invasive skin tumors that grow uncontrollably for a few weeks, but then suddenly shrink and die off, leaving a noncancerous scar.

People with MSSE have a mutation in one copy of the TGFBR1 gene in each cell. An additional mutation in the second copy of the TGFBR1 gene is needed for tumors to form in MSSE. The second mutation, which is called a somatic mutation, is found only in the tumor cells and is not inherited. Unlike TGFBR1 gene mutations that cause Loeys-Dietz syndrome type I (described above), the mutations that cause MSSE prevent the production of any protein at all. A complete lack of functional receptor in certain cells results in a total loss of TGF-β pathway signaling and severely reduced tumor suppression, allowing the skin cancers to form. The mechanism responsible for the spontaneous healing of the multiple skin tumors in MSSE is unknown.

Other Names for This Gene

• serine/threonine-protein kinase receptor R4
• TBR-i
• TBRI
• TGF-beta receptor type I
• TGF-beta receptor type-1
• TGF-beta type I receptor
• TGFR-1
• TGFR1_HUMAN
• transforming growth factor beta receptor I
• transforming growth factor-beta receptor type I

Genomic Location

Normal Function

The WRN gene provides instructions for producing the Werner protein, which plays a critical role in repairing damaged DNA. The Werner protein functions as a type of enzyme called a helicase. Helicase enzymes generally unwind and separate double-stranded DNA. The Werner protein also functions as an enzyme called an exonuclease. Exonucleases trim the broken ends of damaged DNA by removing DNA building blocks (nucleotides). Research suggests that the Werner protein first unwinds the DNA and then removes abnormal DNA structures that have been accidentally generated.

Overall, the Werner protein helps maintain the structure and integrity of a person's DNA. This protein plays an important role in copying (replicating) DNA before cell division and transferring the information in genes to the cell machinery that makes proteins (transcription). Additionally, recent studies suggest that the Werner protein may be particularly important for maintaining DNA at the ends of chromosomes (telomeres).

Health Conditions Related to Genetic Changes

Werner syndrome

More than 60 mutations in the WRN gene are known to cause Werner syndrome. Most of these mutations result in an abnormally short, nonfunctional Werner protein. Research suggests that this shortened protein is not transported into the cell's nucleus, where it normally interacts with DNA. Furthermore, the shortened protein is broken down more quickly than the normal Werner protein, reducing the amount of this protein in the cell. Without normal Werner protein in the nucleus, DNA replication, repair, and transcription are disrupted. Researchers are still determining how mutations in the WRN gene lead to the signs and symptoms of Werner syndrome.

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Cancers

Some changes to a person's genes are acquired during that person's lifetime and are present only in certain cells. These differences, called somatic changes, are not inherited. Somatic changes in the WRN gene are found in nonhereditary tumors and involve a process called methylation. Methylation is a chemical modification that attaches small molecules called methyl groups to certain segments of DNA. When too many methyl groups are attached to the WRN gene (hypermethylation), the gene is turned off and the Werner protein is not produced. Without this protein, cells do not respond normally to DNA damage. The lack of Werner protein allows mutations to accumulate in other genes, which may cause cells to grow and divide in an uncontrolled way. This kind of unregulated cell growth can lead to the formation of cancerous tumors. Hypermethylation of the WRN gene has been found in many different types of tumors, including colon, rectal, lung, stomach, prostate, breast, and thyroid tumors.

Other Names for This Gene

• RECQ3
• RECQL2
• RECQL3
• Werner syndrome
• Werner Syndrome helicase
• Werner syndrome protein
• Werner syndrome, RecQ helicase-like
• WRN_HUMAN

Genomic Location

Normal Function

The WT1 gene provides instructions for making a protein that is necessary for the development of the kidneys and gonads (ovaries in females and testes in males) before birth. After birth, WT1 protein activity is limited to a structure known as the glomerulus, which filters blood through the kidneys. The WT1 protein plays a role in cell growth, the process by which cells mature to perform specific functions (differentiation), and the self-destruction of cells (apoptosis). To carry out these functions, the WT1 protein regulates the activity of other genes by attaching (binding) to specific regions of DNA. On the basis of this action, the WT1 protein is called a transcription factor.

Health Conditions Related to Genetic Changes

Denys-Drash syndrome

Many variants (also known as mutations) in the WT1 gene have been found to cause Denys-Drash syndrome, a condition that affects development of the kidneys and genitalia and most often affects males. These variants are germline, which means they are present in cells throughout the body. The variants that cause Denys-Drash syndrome almost always occur in areas of the gene known as exon 8 and exon 9. Most of these variants result in changes in single protein building blocks (amino acids) in the WT1 protein. The most common variant that causes Denys-Drash syndrome (found in about 40 percent of cases) replaces the amino acid arginine with the amino acid tryptophan at protein position 394 (written Arg394Trp or R394W).

The variants that cause Denys-Drash syndrome lead to the production of an abnormal WT1 protein that cannot bind to DNA. As a result, the activity of certain genes is unregulated, which impairs development of the kidneys and genitalia. Abnormal development of these organs leads to the signs and symptoms of Denys-Drash syndrome.

Rarely, a variant in exon 8 or exon 9 of the WT1 gene causes a related condition called Frasier syndrome (described below). Because these two conditions share a genetic cause and have overlapping features, some researchers have suggested that they are part of a spectrum and not two distinct conditions.

Frasier syndrome

Variants in the WT1 gene have been found to cause Frasier syndrome, a condition that affects development of the kidneys and genitalia and most often affects males. The variants that cause Frasier syndrome are germline and almost always occur in an area of the gene known as intron 9. The most common variant that causes Frasier syndrome (found in over half of affected individuals) changes a single DNA building block (nucleotide) in this area of the gene, written as IVS+4C>T. This variant and others that cause Frasier syndrome alter the way the gene's instructions are pieced together to produce the WT1 protein.

The WT1 gene variants that cause Frasier syndrome lead to the production of a protein with an impaired ability to control gene activity and regulate the development of the kidneys and reproductive organs, resulting in the signs and symptoms of Frasier syndrome.

Rarely, a variant in intron 9 of the WT1 gene causes a related condition called Denys-Drash syndrome (described above). Because these two conditions share a genetic cause and have overlapping features, some researchers have suggested that they are part of a spectrum and not two distinct conditions.

Wilms tumor

Variants in the WT1 gene can cause Wilms tumor, a rare form of kidney cancer that occurs almost exclusively in children. Most of these variants are somatic, which means they are acquired during a person's lifetime and present only in the tumor cells. Other WT1 gene variants are germline.

WT1 gene variants that cause Wilms tumor lead to a WT1 protein with a decreased ability to bind to DNA. As a result, the protein cannot regulate gene activity, leading to uncontrolled growth and division of cells in the kidney and allowing tumor development.

Many conditions caused by germline variants in the WT1 gene, including WAGR syndrome, Denys-Drash syndrome, and Frasier syndrome (described above), are associated with an increased risk of developing Wilms tumor.

WAGR syndrome

The WT1 gene is located in a region of chromosome 11 that is often missing (deleted) in people with WAGR syndrome, which is a disorder that affects many body systems and is named for its main features: a childhood kidney cancer known as Wilms tumor (described below), an eye problem called anirida, genitourinary anomalies, and intellectual disability. This deletion affects one copy of the WT1 gene in each cell. The loss of this gene is responsible for the genitourinary abnormalities and the increased risk of Wilms tumor in affected individuals.

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Other disorders

Germline variants in the WT1 gene have been found to cause Meacham syndrome. This condition is characterized by abnormalities in the development of the male genitalia, heart, and diaphragm. Individuals with this condition have a typical male chromosome pattern (46,XY) but have external genitalia that do not look clearly male or clearly female or have genitalia that appear female-typical. Additionally, the internal reproductive organs are female, but they do not develop normally.

Individuals with Meacham syndrome typically have heart defects of varying severity that are present from birth. They also have a hole in the muscle that separates the abdomen from the chest cavity (the diaphragm), which is called a congenital diaphragmatic hernia. Meacham syndrome is typically fatal in infancy. Approximately a dozen individuals have been diagnosed with Meacham syndrome.

Variants in the WT1 gene can also cause a condition called isolated nephrotic syndrome. This condition is characterized by an inability of the kidneys to filter waste products from the blood, which leads to protein in the urine, swelling (edema) of the abdomen, and ultimately, kidney failure. Isolated nephrotic syndrome includes diffuse glomerulosclerosis, in which scar tissue forms throughout the clusters of tiny blood vessels (glomeruli) in the kidneys, and focal segmental glomerulosclerosis, in which glomeruli in only certain areas of the kidneys experience scarring. Variants in the WT1 gene most often cause diffuse glomerulosclerosis.

Other Names for This Gene

• WIT-2
• WT1_HUMAN
• WT33

Genomic Location