r 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. 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. Some 200 point mutations have been described for Rho and are associated with both adRP and arRP; they have been categorized into six classes with class I and II being the more common. Upon activation, transducin activates the cGMP phoshodiesterase (Pde) complex; the subsequent decrease in cGMP closes the cGMP-gated cation channels resulting in decreased calcium (Ca2+) influx. Mutations in rod-specific Pde and in cGMP-gated channels are associated with arRP. Decrease in intracellular Ca2+ also promotes the activation of guanylate cyclases and restoration of cGMP levels. The enzymes are constitutively bound to activator proteins (GCAPs), Ca2+ binding proteins that inhibit the cyclases in the presence of Ca2+ but stimulate them in its absence. Mutations in an activator gene have been associated with adRP. GPCR signaling is controlled by several classes of proteins - the kinases that phosphorylate the activated receptors which are then recognized by arrestins whose binding precludes re-binding of G-proteins; at the G-protein level, by GTPase-activating proteins (GAPs) that increase the rate of G-protein GTP hydrolysis leading to inactivation of the Galpha subunit. Sag is a specific arrestin whose mutations have been associated with arRP. 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. Several enzymes catalyze the transformation of substrates back to the 11-cis retinal in the metabolic visual cycle. 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 Abca4 transporter. All-trans retinol is esterified to retinyl esters by Lrat. Isomerization to 11-cis retinol is carried out by Rbp65. Retinols are bound by Rbp3 in the extracellular space and by Rbp1 in the retinal pigment epithelium (RPE). Oxidation of 11-cis retinol to 11-cis retinal is carried out by 11-cis retinol dehydrogenases; the newly synthesized chromophore is bound by Rlbp1 which mediates its transport to the receptor site on the membrane. Many of these genes carry mutations and are associated with RP and other forms of photoreceptor degeneration. Approximately one sixth of all RP patients have Usher (USH) syndrome characterized by both vision and hearing loss. Clinically, the three types of Usher - USH1, 2 and 3 have been associated with five, three and one gene, respectively; USH1 is the most severe form. The five genes in USH1 - collectively referred to as the USH1 interactome - are implicated in arRP along with one USH2 and the one USH3 gene. Their associations with auditory mechanotransduction are better known - see the auditory mechanotransduction pathway; the precise roles in visual phototransduction and altered pathways are still elusive but impaired ciliary transport/trafficking is possible. Other RP and photoreceptor degeneration disorders associated genes affect process/pathway categories such as ciliary transport and channel activity, retinal development, metabolism and splicing (several are listed). The expression and targets of several microRNAs are important for the eye. Aberrant expression of several miRNAs has been observed in mouse models of RP where the relatively few studies of miRNAs roles in photoreceptor degeneration have been carried out. To see the ontology report for annotations, Gviewer and download, click here...(less)