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Retinitis Pigmentosa Pathway

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 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 classified. 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. 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.


References Associated with the retinitis pigmentosa pathway:

Daiger SP, et al. | Clin Genet | 2013 Aug | 84(2) | 132-41 | doi: 10.1111/cge.12203

Wright AF, et al. | Nat Rev Genet | 2010 Apr | 11(4) | 273-84 | doi: 10.1038/nrg2717

Athanasiou D, et al. | FEBS Lett | 2013 Jun 27 | 587(13) | 2008-17 | doi: 10.1016/j.febslet.2013.05.020

Mendes HF, et al. | Trends Mol Med | 2005 Apr | 11(4) | 177-85

Jones BW, et al. | Jpn J Ophthalmoly | 2012 July | 56(4) | 289-306 | doi: 10.1007/s10384-012-0147-2

Petrs-Silva H and Linden R | Clin Ophthalmoly | 2014 | 8:127-136.

Estrada-Cuzcano A, et al. | Hum Mol Genet | 2012 Oct 15 | 21(R1) | R111-24

Xu S | Prog Retin Eye Res | 2009 Mar | 28(2) | 87-116 | doi: 10.1016/j.preteyeres.2008.11.003

Liu MM, et al. | Curr Genomics | 2013 May | 14(3) | 166-72 | doi: 10.2174/1389202911314030002

Huang KM, et al. | Mamm Genome | 2008 Aug | 19(7-8) | 510-6 | doi: 10.1007/s00335-008-9127-8

Pan L and Zhang M | Physiology (Bethesda) | 2012 Feb | 27(1) | 25-42 | doi: 10.1152/physiol.00037.2011


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