Aniridia is an eye disorder characterized by a complete or partial absence of the colored part of the eye (the iris). These iris abnormalities may cause the pupils to be abnormal or misshapen. Aniridia can cause reduction in the sharpness of vision (visual acuity) and increased sensitivity to light (photophobia).

People with aniridia can also have other eye problems. Increased pressure in the eye (glaucoma) typically appears in late childhood or early adolescence. Clouding of the lens of the eye (cataracts), occur in 50 percent to 85 percent of people with aniridia. In about 10 percent of affected people, the structures that carry information from the eyes to the brain (optic nerves) are underdeveloped. Individuals with aniridia may also have involuntary eye movements (nystagmus) or underdevelopment of the region at the back of the eye responsible for sharp central vision (foveal hypoplasia). Many of these eye problems contribute to progressive vision loss in affected individuals. The severity of symptoms is typically the same in both eyes.

Rarely, people with aniridia have behavioral problems, developmental delay, and problems detecting odors.

Aniridia is caused by mutations in the PAX6 gene. The PAX6 gene provides instructions for making a protein that is involved in the early development of the eyes, brain and spinal cord (central nervous system), and the pancreas. Within the brain, the PAX6 protein is involved in the development of a specialized group of brain cells that process smell (the olfactory bulb). The PAX6 protein attaches (binds) to specific regions of DNA and regulates the activity of other genes. On the basis of this role, the PAX6 protein is called a transcription factor. Following birth, the PAX6 protein regulates several genes that likely contribute to the maintenance of different eye structures.

Mutations in the PAX6 gene result in the production of a nonfunctional PAX6 protein that is unable to bind to DNA and regulate the activity of other genes. A lack of functional PAX6 protein disrupts the formation of the eyes during embryonic development.

Normal Function

The PAX6 gene belongs to a family of genes that play a critical role in the formation of tissues and organs during embryonic development. The members of the PAX gene family are also important for maintaining the normal function of certain cells after birth. To carry out these roles, the PAX genes provide instructions for making proteins that attach to specific areas of DNA and help control the activity (expression) of particular genes. On the basis of this action, PAX proteins are called transcription factors.

During embryonic development, the PAX6 protein is thought to turn on (activate) genes involved in the formation of the eyes, the brain and spinal cord (central nervous system), and the pancreas. Within the brain, the PAX6 protein is involved in the development of a specialized group of brain cells that process smell (the olfactory bulb). Additionally, researchers believe that the PAX6 protein controls many aspects of eye development before birth. After birth, the PAX6 protein likely regulates the expression of various genes in many structures of the eyes.

Health Conditions Related to Genetic Changes

Aniridia

More than 280 mutations in the PAX6 gene have been found to cause aniridia, which is an absence of the colored part of the eye (the iris). Most of these mutations create a premature stop signal in the instructions for making the PAX6 protein and lead to the production of an abnormally short, nonfunctional protein. As a result, there is less PAX6 protein to regulate the activity of other genes.

The majority of mutations that cause aniridia occur within the PAX6 gene; however, some disease-causing mutations occur in neighboring regions of DNA that normally regulate the expression of the PAX6 gene, known as regulatory regions. Mutations in PAX6 gene regulatory regions reduce the expression of the PAX6 gene. These mutations lead to a shortage of functional PAX6 protein, which disrupts the formation of the eyes during development.

Peters anomaly

At least two mutations in the PAX6 gene have been found to cause Peters anomaly. This condition is characterized by the abnormal development of certain structures at the front of the eye and clouding of the clear front surface of the eye (cornea). The mutations that cause Peters anomaly change single protein building blocks (amino acids) in the PAX6 protein. These mutations reduce but do not eliminate the protein's function and are less severe than mutations that cause aniridia (described above). The mutations that cause Peters anomaly reduce the PAX6 protein's ability to bind to DNA, disrupting its role as a transcription factor. As a result, normal development of the eye is impaired, leading to the features of Peters anomaly. The PAX6 gene mutations that cause Peters anomaly can cause other related eye disorders in members of the same family.

Coloboma

Mutations in the PAX6 gene can cause an eye problem called coloboma, in which there is a gap or split in one of the structures that make up the eye. The mutations that cause this abnormality occur in one copy of the PAX6 gene in each cell. Most of these mutations change single amino acids in the PAX6 protein. These mutations reduce but do not eliminate the protein's normal function, impairing its role as a transcription factor.

Microphthalmia

Mutations in one copy of the PAX6 gene can cause microphthalmia, which describes eyes that are smaller than usual. These genetic changes reduce but do not eliminate PAX6 protein function. As a result, the PAX6 protein is less able to control the activity of certain genes involved in eye development.

WAGR syndrome

The PAX6 gene is located in a region of chromosome 11 that is 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, an eye problem called anirida, genitourinary anomalies, and intellectual disability (formerly referred to as mental retardation). As a result of this deletion, affected individuals are missing one copy of the PAX6 gene in each cell. A loss of the PAX6 gene is associated with the characteristic eye features of WAGR syndrome, including aniridia, and may affect brain development.

Other disorders

Mutations in the PAX6 gene can cause a variety of eye problems. Most of these mutations change single amino acids in the PAX6 protein. These mutations reduce but do not eliminate the protein's normal function, impairing its role as a transcription factor.

In addition to microphthalmia or coloboma (described above), individuals with these relatively mild PAX6 gene mutations may be born with pupils that are not centrally positioned in the eye (ectopia papillae) or underdeveloped optic nerves, which are the structures that carry information from the eyes to the brain. Mild PAX6 mutations can also result in underdevelopment of the region at the back of the eye responsible for sharp central vision (the fovea). Additional conditions caused by these PAX6 gene mutations may be present at birth or develop later. These conditions may include a clouding of the lens of the eye (cataracts), involuntary eye movements (nystagmus), and inflammation of the front surface of the eye called the cornea (keratitis).

It is unclear why the effects of some mutations in the PAX6 gene are limited to the eye, while other mutations affect the development of many parts of the body.

Other Names for This Gene

• AN
• AN2
• D11S812E
• MGC17209
• MGDA
• paired box gene 6
• paired box gene 6 isoform a
• paired box gene 6 isoform b
• PAX6_HUMAN

Genomic Location

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

In approximately two-thirds of cases, an affected person inherits the mutation from one affected parent. The remaining one-third of cases result from new mutations in the gene and occur in people with no history of the disorder in their family.

Prenatal testing is available for pregnancies at increased risk for aniridia if the disease-causing mutation of an affected family member has been identified. Current clinically available testing can detect up 79.5% of mutation that cause isolated aniridia and 71% of mutations that cause WAGR syndrome. Detection rates, however, can potentially improve over time.

Aniridia occurs in 1 in 50,000 to 100,000 newborns worldwide.