Photoreceptor cells are susceptible to cellular stress - their degeneration and loss is a major cause of blindness. Many genes have identified for the inherited and highly heterogeneous disorders resulting from photoreceptor degeneration. One of the most common form is retinitis pigmentosa (RP) and its patterns of inheritance are varied - some are autosomal dominant (adRP), others are autosomal recessive (arRP), a smaller fraction are X-linked (XLRP) and between 30 to 50% have not yet been class
ified. Other disorders include Bardet-Biedl syndrome (BBS), macular and age-related macular degeneration (MD, AMD), Leber congenital amaurosis (LCA), cone and cone-rod degeneration (CD, CRD). RP may occur alone or non-syndromic or in combination with other disorders, such as the Usher syndrome. Mutations in the same gene can cause different phenotypes, such as the many mutations in rhodopsin receptor (Rho) that cause adRP or arRP. Many RP mutations are in genes involved in the phototransduction and the metabolic visual cycle pathways. To access the diagram for the normal retinoid cycle pathway, click here . The response to light in the vertebrate retina is mediated by two photoreceptor types: the rods that mediate vision in dim light and the cones that mediate bright light and color vision. Both are G-protein coupled receptors (GPCR) that activate the specific heterotrimeric G protein transducin complex upon their own activation by the visual pigment - the vitamin A-derived 11-cis retinal. The one rod gene (Rho) and three cone genes are collectively known as opsins. In the absence of light, 11-cis retinal acts as an inverse agonist that constrains the receptor in an inactive conformation. Upon light stimulation, the chromophore is isomerized to all-trans retinal; a series of conformational changes in the photoreceptor follow and the isomerized chromophore is released. Several enzymes catalyze the reduction, esterification, isomerization and final oxidation of substrates back to the 11-cis retinal in the metabolic visual cycle to assure the continued visual phototransduction response to light. Briefly, all-trans retinal is first reduced to all-trans retinol by specific retinol dehydrogenases (RDHs); its transport to the cytoplasmic side of the membrane to serve as the substrate of the enzymes is mediated by the ATP-binding cassette transporter Abca4. All-trans retinol is esterified to retinyl esters by Lrat. Isomerization of all-trans retinol/retinyl esters to 11-cis retinol is carried out by Rpe65. Retinols are bound by Rbp3 in the extracellular space and by Rbp1 in the retinal pigment epithelium (RPE). The oxidation of 11-cis retinol to 11-cis retinal is carried by 11-cis retinol dehydrogenases; the newly synthesized chromophore is bound by Rlbp1 which mediates its transport to the receptor site on the membrane. Mutations in many of the genes in the visual cycle have been associated with both the arRP and adRP and with other forms of photoreceptors degeneration. The genes whose mutations display a dominant phenotype are highlighted. In addition to the mutant genes in this and the visual phototransduction pathway, other RP and photoreceptor degeneration disorders associated genes affect process/pathway categories such as ciliary transport and channel activity, retinal development, metabolism and splicing (see other genes in RP in the disease pathway). Impairment of the visual cycle can deplete the system of 11-cis retinal production and therefore of the continued phototransduction response to light. Combined with rod defective visual transduction it can result in decreased input to the visual cortex and diminished visual perception. Its augmentation with time may underlie the progressive degeneration of the photoreceptor and associated blindness. To see the ontology report for annotations, Gviewer and download, click here...(less)
