Wagner syndrome is a hereditary disorder that causes progressive vision loss. The eye problems that lead to vision loss typically begin in childhood, although the vision impairment might not be immediately apparent.

In people with Wagner syndrome, the light-sensitive tissue that lines the back of the eye (the retina) becomes thin and may separate from the back of the eye (retinal detachment). The blood vessels within the retina (known as the choroid) may also be abnormal. The retina and the choroid progressively break down (degenerate). Some people with Wagner syndrome have blurred vision because of ectopic fovea, an abnormality in which the part of the retina responsible for sharp central vision is out of place. Additionally, the thick, clear gel that fills the eyeball (the vitreous) becomes watery and thin. People with Wagner syndrome develop a clouding of the lens of the eye (cataract). Affected individuals may also experience nearsightedness (myopia), progressive night blindness, or a narrowing of their field of vision.

Vision impairment in people with Wagner syndrome can vary from near normal vision to complete loss of vision in both eyes.

Mutations in the VCAN gene cause Wagner syndrome. The VCAN gene provides instructions for making a protein called versican. Versican is found in the extracellular matrix, which is the intricate lattice of proteins and other molecules that forms in the spaces between cells. Versican interacts with many of these proteins and molecules to facilitate the assembly of the extracellular matrix and ensure its stability. Within the eye, versican interacts with other proteins to maintain the structure and gel-like consistency of the vitreous.

VCAN gene mutations that cause Wagner syndrome lead to insufficient levels of versican in the vitreous. Without enough versican to interact with the many proteins of the vitreous, the structure becomes unstable. This lack of stability in the vitreous affects other areas of the eye and contributes to the vision problems that occur in people with Wagner syndrome. It is unknown why VCAN gene mutations seem solely to affect vision.

Normal Function

The VCAN gene provides instructions for making a protein called versican. Versican is a type of protein known as a proteoglycan, which means it has several sugar molecules attached to it. Versican is found in the extracellular matrix of many different tissues and organs. The extracellular matrix is the intricate lattice of proteins and other molecules that forms in the spaces between cells. Versican interacts with many proteins and molecules to facilitate the assembly of the extracellular matrix and ensure its stability. Within the eye, versican interacts with other proteins to maintain the structure and gel-like consistency of the thick clear fluid that fills the eyeball (the vitreous).

Researchers have proposed several additional functions for versican. This protein likely helps regulate cell growth and division, the attachment of cells to one another (cell adhesion), and cell movement (migration). Studies suggest that versican plays a role in forming new blood vessels (angiogenesis), wound healing, inflammation, and preventing the growth of cancerous tumors. Versican also regulates the activity of several growth factors, which control a diverse range of processes important for cell growth.

Four different versions (isoforms) of the versican protein are produced from the VCAN gene. These isoforms (called V0, V1, V2, and V3) vary by size and by their location within the body.

Health Conditions Related to Genetic Changes

Wagner syndrome

At least 11 mutations in the VCAN gene have been found to cause Wagner syndrome, a condition that leads to progressive vision loss starting in childhood or early adulthood. The VCAN gene mutations that cause Wagner syndrome disrupt the way the gene's instructions are used to make versican. These mutations occur in two areas of the gene called intron 7 and exon 8; mutations in these regions lead to a decrease in the production of versican isoforms V0 and V1 and an increase in the production of isoforms V2 and V3. Researchers believe that this imbalance of versican isoforms in the vitreous impairs versican's interaction with other proteins, causing the vitreous to become unstable. This lack of stability in the vitreous affects other areas of the eye and contributes to the vision problems that occur in people with Wagner syndrome. It is unknown why VCAN gene mutations seem solely to affect vision.

Other Names for This Gene

• chondroitin sulfate proteoglycan 2
• CSPG2
• CSPG2_HUMAN
• glial hyaluronate-binding protein
• versican proteoglycan

Genomic Location

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.

• Early cataracts (before age 40)
• Degeneration and atrophy of the retina, the underlying retinal pigment epithelium (RPE), and the choroid
• Retinal detachment
• Nearsightedness (myopia)
• Night blindness
• Visual field restriction

Wagner syndrome is a rare disorder, although its exact prevalence is unknown. Approximately 300 affected individuals have been described worldwide; about half of these individuals are from the Netherlands.