Achromatopsia (achromatopsia) - Genes CNGA3, CNGB3, GNAT2, PDE6C, or PDE6H.

Achromatopsia is a disorder of the retina characterized by a partial or total absence of color vision. People with complete color blindness can not see colors, see only black, white and shades of gray. For its part, incomplete achromatopsia is a milder form of the disorder that allows some color discrimination.

Achromatopsia also involves other problems with vision, including photophobia, nystagmus and low visual acuity. Affected individuals may also have farsightedness or, less frequently, myopia. These vision problems develop in the first months of life. Achromatopsia is different from the most common forms of color blindness, in which people can perceive color, but have difficulty distinguishing between certain colors, like red and green.

The retina contains two types of light receptor cells, called rods and cones. These cells transmit visual signals from the eye to the brain through a process called phototransduction. Canes provide vision in low light conditions, while cones provide vision in bright light conditions, including color vision. This process is due to mutations in the CNGA3, CNGB3, GNAT2, PDE6C or PDE6H genes.

Mutations in any of the above mentioned genes prevent the cones react to light properly, which interferes with phototransduction. In people with complete achromatopsia, the cones are not functional, and vision depends entirely on the activity of the rods. The loss of function of the cones results in a complete lack of color vision and cause other vision problems. Individuals with incomplete achromatopsia retain some function of the cones. These individuals have a vision of limited colors, and other vision problems tend to be less severe. In some people with color blindness have not identified mutations in any of the known genes, and these individuals, the cause of the disease is unknown. Other genetic factors have not been identified likely contribute to this condition.

The CNGA3 gene, located on the long arm of chromosome 2 (2q11.2), and CNGB3 gene, located on the long arm of chromosome 8 (8q21.3) encoding the alpha subunit of the CNG channel. These channels are found exclusively in photoreceptors called cones, which are found in the retina. CNG channels are openings in the cell membrane carrying cation cells. In cones, CNG channels are open in the dark, allowing the cations to flow. When light enters the eye, the closure of these channels is triggered, stopping the flow of cations. This change in cation transport alters the electrical charge of the cone, which ultimately generates a signal that is interpreted by the brain as vision. This translation process light into an electrical signal called phototransduction.

There are more than 100 mutations in the gene CNGA3 and more than 40 mutations in the gene CNGB3 in people with achromatopsia. Mutations in the gene CNGA3 represent about 25% of cases of complete achromatopsia. However, we have identified mutations of this gene in a few individuals with incomplete achromatopsia. Mutations in the gene CNGA3 affect coding or function of the alpha subunit. In some cases, the protein is not encoded. In others, the protein is altered and it operates abnormally. CNG channels assembled without the alpha subunit or a functional subunit not prevent cones carried out phototransduction. It is believed that some defective channels allow a large influx of cations in the cones, which ultimately causes apoptosis of these cells. Meanwhile, mutations in the gene CNGB3 represent between 50% and 70% of cases of complete achromatopsia. The most common mutation eliminates one base pair gene CNGB3 (1148delC). Another identified mutation replaces the amino acid serine with phenylalanine at amino acid position 435 in the protein (or Ser435Phe S435F). Most mutations encoding prevent any functional beta subunit, which alters the structure of the CNG channels.

The GNAT2 gene, located on the short arm of chromosome 1 (1p13.1), encodes an alpha subunit of a protein called transducin. This protein is found in the retinal photoreceptors called cones. Transducin protein plays an essential role in phototransduction. Photoreceptors contain photo pigments that absorb light. These photopigments activated transducin, which triggers a series of chemical reactions within the cell. These reactions alter the electrical charge of the cell and ultimately generate a signal that is interpreted by the brain as vision. They have identified at least 10 mutations in the gene GNAT2 in people with achromatopsia. These mutations result in an abnormally small version, no functional alpha subunit of transducin. Without this subunit, they have no functional cones transducin, and are not able to carry out phototransduction. At least one mutation of the gene GNAT2 (461 + 2G> A) causes incomplete achromatopsia. This mutation allows the encoding of some functional alpha subunits. As a result, a small amount of functional transducin is available to play its role in phototransduction, and partially functioning cones can transmit any visual information to the brain.

The PDE6C gene, located on the long arm of chromosome 10 (10q24), and PDE6H gene, located on the short arm of chromosome 12 (12p13), encoding a portion of an enzyme called phosphodiesterase-specific cone. This enzyme is found exclusively in the cones. Specifically, the enzyme converts a molecule to another molecule called cGMP, 5'-GMP, in cones. This conversion makes certain channels in the cell membrane close. The closure of these channels causes transmission of visual signals to the brain. They have identified at least 19 mutations in the gene PDE6C and at least one mutation in the gene PDE6H in people with achromatopsia. Mutations in the gene PDE6C represent a relatively small percentage of cases of complete and incomplete achromatopsia. These mutations affect the function of the alpha-prime subunit. Mutations that result in the complete achromatopsia eliminate phosphodiesterase activity, which aborts the phototransduction in cones. Mutations in the gene PDE6C reduced but not eliminated the phosphodiesterase activity cause incomplete achromatopsia. Meanwhile, the mutation identified in PDE6H gene replaces an amino acid that stops encoding proteins (or Ser12Ter S12X). This change prevents any subunit encoding functional inhibitory gamma, which interferes with the normal function of phosphodiesterase-specific cone.

This disease is inherited in an autosomal recessive pattern, that is, 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.

Tests in IVAMI: in IVAMI perform detection of mutations associated with achromatopsia, by complete PCR amplification delos delos CNGA3 exons, CNGB3, GNAT2, and PDE6C PDE6H genes, 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).