Frasier syndrome is a condition that affects the kidneys and genitalia.

Frasier syndrome is characterized by kidney disease that begins in early childhood. Affected individuals have a condition called focal segmental glomerulosclerosis, in which scar tissue forms in some glomeruli, which are the tiny blood vessels in the kidneys that filter waste from blood. In people with Frasier syndrome, this condition often leads to kidney failure by adolescence.

Although males with Frasier syndrome have the typical male chromosome pattern (46,XY), they have gonadal dysgenesis, in which external genitalia do not look clearly male or clearly female or the genitalia appear female-typical. The internal reproductive organs (gonads) are typically undeveloped and referred to as streak gonads. These abnormal gonads are nonfunctional and often become cancerous, so they are usually removed surgically early in life.

Affected females usually have normal genitalia and gonads and have only the kidney features of the condition. Because they do not have all the features of the condition, females are usually given the diagnosis of isolated nephrotic syndrome.

Mutations in the WT1 gene cause Frasier syndrome. The WT1 gene provides instructions for making a protein that 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. The WT1 protein plays a role in the development of the kidneys and gonads (ovaries in females and testes in males) before birth.

The WT1 gene mutations 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.

Frasier syndrome has features similar to another condition called Denys-Drash syndrome, which is also caused by mutations in the WT1 gene. 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.

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

Frasier syndrome is thought to be a rare condition; approximately 50 cases have been described in the scientific literature.

This condition is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder.