Vitreoretinopathy familial exudative (exudative vitreoretinopathy Familial) - Genes FZD4, LRP5 and NDP.
Familial exudative vitreoretinopathy is an inherited disorder that can cause progressive loss of vision, retinal involvement. Alteration prevents the formation of blood vessels in the retina margins, reducing blood supply to the tissue.
Signs and symptoms of familial exudative vitreoretinopathy vary widely, even within the same family. In many affected individuals, changes in the retina do not cause any vision problems. In others, a reduction in blood supply to the retina causes the retina bend, break or detachment occurs. This retinal damage can lead to vision loss and blindness. Other ocular abnormalities are also possible, including strabismus and leucocoria in the pupil. Some people with this disease have also reduced bone mineral density, that weakens bones and increases the risk of fractures.
This process is due to mutations in FZD4, LRP5, and NDP genes. These genes encode proteins involved in a signaling pathway involving chemical form in which cells and tissues develop. In particular, the proteins produced from the FZD4, LRP5, and NDP genes appear to play critical roles in the specialization of retinal cells and the establishment of a blood supply to the retina , and inner ear. The LRP5 protein also helps regulate bone formation. Mutations in these genes disrupt chemical signaling during early development, which interferes with the formation of blood vessels in the retina margins. Abnormal blood supply of this tissue leads to retinal damage and vision loss in some people with familial exudative vitreoretinopathy.
Ocular abnormalities associated with familial exudative vitreoretinopathy the tend to be similar whether it is affected. However, affected individuals with gene mutations LRP5 often reduce bone mineral density, in addition to the loss of vision. Mutations in other genes responsible for familial exudative vitreoretinopathy the not appear to affect bone density.
The FZD4 gene, located on the long arm of chromosome 11 (11q14.2), encoding the curly-4 protein. This protein is embedded in the outer membrane of many cell types, where it is involved in the transmission of chemical signals from outside the cell to the cell nucleus. Specifically, frizzled-4 is involved in the Wnt signaling pathway, a series of steps involving the development of cells and tissues. Wnt signaling is important for the proliferation, adhesion, migration, and many other cellular activities. It appears that cell surface protein frizzled-4 interacts with a protein called Norrin (NDP produced from the gene). During early development, Norrin signaling and frizzled-4 plays a critical role in the specialization of cells in the retina. This signaling pathway is also involved in establishing a blood supply to the retina and inner ear.
There are more than 20 mutations in the gene FZD4 causing familial exudative vitreoretinopathy. Some of these mutations change some encoding nucleotide frizzled-4 protein, whereas other genetic material inserted or deleted in the gene. Most mutations reduce the amount of frizzled-4 produced within the cells. It is believed that other mutations result in the production of an unstable protein can not bind to Norrin. A reduction in the amount of frizzled-4 interrupts chemical signaling in the developing eye, which interferes with the formation of blood vessels in the retina margins. Abnormal blood supply resulting from this abnormal tissue leads to retinal damage and vision loss in some people.
The LRP5 gene, located on the long arm of chromosome 11 (11q13.4), encodes an embedded in the outer membrane of many cell types protein. This protein plays an important role in the development and maintenance of various tissues. It is also involved in establishing a blood supply to the retina and inner ear. Furthermore, this protein helps regulate bone mineral density, a measure of the amount of calcium and other minerals in the bones.
They have identified more than 15 mutations in the LRP5 gene causing the disease. Some of these mutations change nucleotides encoding the amino acids of the protein, whereas other genetic material inserted or deleted in the gene. Most of these mutations reduce the amount of functional protein is produced within the cells. A reduction in the amount of protein interrupts chemical signaling in the development of the eye, interferes with the formation of blood vessels in the retina margins. Abnormal blood supply resulting from this tissue can lead to retinal damage and vision loss. Because the protein plays a role in bone formation, LRP5 gene mutations also cause a reduction in bone mineral density in some people with the disease. Changes in the LRP5 gene may influence the risk of developing osteoporosis in adulthood.
The NDP gene, located on the short arm of X (Xp11.4) chromosome, encodes the protein Norrin. Mutations in this gene, change the nucleotides encoding the amino acids of the protein Norrin, disrupting normal folding or preventing its binding to Frizzled-4. Consequently, this altered protein that eventually causes some tissues deteriorate.
This disease has different inheritance patterns depending on the gene involved. Usually cases arising from mutations in the gene LRP5 FZD4 or have a pattern of autosomal dominant, which means a copy of the altered gene in each cell is sufficient to cause the disorder. Most people with autosomal dominant familial exudative vitreoretinopathy inherited the altered gene from one parent, but the parent may not have any signs and symptoms associated with this condition.
Where derivatives LRP5 gene mutations may also have an autosomal recessive inheritance pattern, which means that both copies of the gene in every cell must have mutations for alteration is expressed. The parents of an individual with an autosomal recessive disease have a copy of the mutated gene, but usually show no signs and symptoms of the disease.
When the disease is caused by mutations in the gene NDP, it has a pattern of inheritance X - linked gene The NDP is on the X chromosome, one of the two sex chromosomes. In males, who have only one X chromosome, an altered copy of the gene in each cell it is sufficient to cause disease. In women, who have two X chromosomes, the mutation would have to happen in both copies of the gene to cause the disorder.
Tests in IVAMI: in IVAMI perform detection of mutations associated with familial exudative vitreoretinopathy, by complete PCR amplification of the exons of FZD4, LRP5 genes, and NDP respectively and subsequent sequencing.
Samples recommended: EDTA blood collected for separation of blood leukocytes, or impregnated sample card with dried blood (IVAMI may mail the card to deposit the blood sample).