Instituto Valenciano de Microbiología

Masía El Romeral
Ctra. de Bétera a San Antonio Km. 0.3
46117 Bétera (Valencia)
Phone. 96 169 17 02
Fax 96 169 16 37
CIF B-96337217


Retinitis pigmentosa (retinitis pigmentosa) - Genes RHO, USH2A, RPGR and RP2  

Retinitis pigmentosa is a group of related eye disorders that lead to a progressive loss of vision as a result of a gradual deterioration of the retina. Usually the first sign of this change is a loss of night vision, which becomes evident in childhood. Later, the disease causes the development of blind spots in the peripheral vision. Over time, these blind spots come together to produce tunnel vision.

Increasingly, the signs and symptoms of retinitis pigmentosa limited to loss of vision. In this regard, we have identified several types of non - syndromic retinitis pigmentosa, usually distinguished by their pattern of inheritance: autosomal dominant, autosomal recessive or X - linked Less often, this disease occurs as part syndromes that affect other organs and tissues in the body, so it is called syndromic retinitis pigmentosa. The most common form of syndromic retinitis pigmentosa Usher syndrome is characterized by the combination of loss of vision and hearing loss starting at an early age. Retinitis pigmentosa is also a characteristic of several other genetic syndromes, including Bardet-Biedl syndrome, Refsum disease and neuropathy, ataxia and retinitis pigmentosa (NARP).

Mutations have been identified in more than 60 genes that lead to development of non - syndromic retinitis pigmentosa. Over 20 of these genes they are associated with autosomal dominant form of the disease. Mutations in the gene RHO (rhodopsin) are the most common cause autosomal dominant retinitis pigmentosa, representing 20 to 30% of all cases. At least 35 genes have been associated with the autosomal recessive form of the disease, the most frequent USH2A gene (usherin), whose mutations are responsible for 10 to 15% of all cases of retinitis pigmentosa autosomal recessive. It is believed that changes in at least six genes result in X - linked form of the disease. Together, mutations in the genes RPGR (retinitis pigmentosa GTPase regulator) and RP2 (Retinitis pigmentosa 2, X-linked recessive) represent the most cases of retinitis pigmentosa X - linked

RHO (rhodopsin) gene, located on the long arm of chromosome 3 (3q22.1), encodes rhodopsin protein necessary for normal vision, particularly in low light conditions. Rhodopsin is found in specialized cells for light poles. As part of the retina, the rods provide vision in low light conditions. Other light receptor cells in the retina, the cones are responsible for vision in bright light. Rhodopsin protein is bound to a molecule called 11-cis-retinal, which is a form of vitamin A. When light access this molecule, rhodopsin is activated and a series of chemical reactions that create electrical signals are launched . These signals are transmitted to the brain where they are interpreted as vision.

They have identified more than 150 mutations in the RHO gene in people with retinitis pigmentosa. Mutations in this gene, represent between 20 and 30% of all cases of retinitis pigmentosa autosomal dominant, so is believed to be the most frequent form of the disease. Rarely, mutations in this gene result in autosomal recessive form. Most RHO gene mutations alter the folding or transport protein rhodopsin. Some mutations cause rhodopsin be constitutively active instead of being activated in response to light. Studies suggest that altered versions of rhodopsin interfere with essential cellular functions, causing cell apoptosis canes. Retinitis pigmentosa is also associated with a gradual loss of cone cells. The death of these cells causes tunnel vision and ultimately blindness in many affected individuals. It is unclear how mutations in the gene RHO affect the function and survival of cone cells.

The USH2A (usherin) gene, located on the long arm of chromosome 1 (1q41), encoding the protein usherin. Although usherin function has not been well elucidated, studies suggest that it is part of a protein complex that plays an important role in the inner ear and the development of the retina. In these places, the protein complex can also be involved in the function of synapses. They have identified several dozen mutations in the gene USH2A in people with retinitis pigmentosa. The most frequent mutations in the gene USH2A are responsible for the autosomal recessive form, representing between 10 and 15% of all cases. These mutations consist of amino acid changes in usherin protein, and involve the gradual breakdown of the retinal photoreceptors. Progressive vision loss characteristic of this disorder is due to loss of these cells.

The RPGR gene (retinitis pigmentosa GTPase regulator), located on the short arm of the X (Xp21.1) chromosome, encodes a protein that is essential for normal vision. Although the function of the protein is not well understood, it is suggested to play an important role in cilia, involved in cell movement and in many different chemical signaling pathways. Cilia are also necessary for the perception of sensory information, including sound, smell and vision. Several isoforms of the protein are encoded RPGR from RPGR gene. One of these isoforms contains a segment known as exon ORF15. This version of the RPGR protein is predominantly expressed in the retina, photoreceptors specifically. It is believed that this isoform may help maintain photoreceptor by regulating the function of cilia. They have been described over 300 mutations in the RPGR gene in individuals with retinitis pigmentosa X - linked mutations in this gene primarily affecting males, resulting in night blindness in infancy, followed by a progressive loss of vision daytime. Mutations in the gene RPGR represent about 70% of all cases of retinitis pigmentosa X - linked Most mutations responsible for retinitis pigmentosa X - linked occur in exon ORF15 protein. These mutations usually result in synthesis of an abnormally short, nonfunctional protein which disrupts the normal function of the cilia in the photoreceptor cells.

The gene RP2 (Retinitis pigmentosa 2, X-linked recessive), located on the short arm of the X (Xp11.3) chromosome, encodes a protein that is essential for normal vision. The protein is active in cells throughout the body, including the cells that make up the retina. Studies suggest that may be involved in protein transport within photoreceptors. They have identified more than 70 mutations in the RP2 gene in people with X - linked form of retinitis pigmentosa. This disorder mainly affects males, which causes night blindness in infancy, followed by a progressive loss of day vision. RP2 gene mutations represent between 10 and 15% of all cases of retinitis pigmentosa X - linked Most mutations in this gene, resulting in the synthesis of an abnormally short version of the protein, although some consist of amino acid changes in protein RP2. These changes alter the structure and function of the protein, which probably affects the stability or maintenance of photoreceptor cells. A progressive loss of these cells leads to progressive vision loss characteristic of retinitis pigmentosa.  

Most often, retinitis pigmentosa has an autosomal dominant inheritance, which means that a copy of an altered gene in each cell is sufficient to express the process. Most people with autosomal dominant retinitis pigmentosa have an affected parent and other family members. Retinitis pigmentosa 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. In addition, the disease can be inherited an X chromosome - linked pattern, when the genes are on the X chromosome in males, an altered copy of the gene in each cell is sufficient to express the disease. In women, usually mutations must occur in both copies of the gene for the disease manifests itself. However, at least 20% of women who carry one mutated copy of the gene may develop retinal degeneration and vision loss. In most cases, men have more severe symptoms of the disease than women. A feature of the X - linked inheritance is that fathers can not pass X - linked traits to their sons chromosome. In 10 to 40% of all cases of retinitis pigmentosa, only one person in a family is affected. In these families, the process is described as "simple". It can be difficult to determine the inheritance pattern of "simple" cases because affected individuals may not have affected relatives or may not be aware of other family members with the disease. Cases "simple" can also be caused by a new mutation of the gene that is not present in other family members.  

Tests in IVAMI: in IVAMI perform detection of mutations associated with retinitis pigmentosa, by complete PCR amplification of the exons of the RHO, USH2A, RPGR and RP2, respectively, genes 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).