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• W2051283183 abstract "Retinitis pigmentosa (RP) is a group of genetically and clinically heterogeneous inherited degenerative retinopathies caused by abnormalities of photoreceptors or retinal pigment epithelium in the retina leading to progressive sight loss. Rhodopsin is the prototypical G-protein-coupled receptor located in the vertebrate retina and is responsible for dim light vision. Here, novel M39R and N55K variants were identified as causing an intriguing sector phenotype of RP in affected patients, with selective degeneration in the inferior retina. To gain insights into the molecular aspects associated with this sector RP phenotype, whose molecular mechanism remains elusive, the mutations were constructed by site-directed mutagenesis, expressed in heterologous systems, and studied by biochemical, spectroscopic, and functional assays. M39R and N55K opsins had variable degrees of chromophore regeneration when compared with WT opsin but showed no gross structural misfolding or altered trafficking. M39R showed a faster rate for transducin activation than WT rhodopsin with a faster metarhodopsinII decay, whereas N55K presented a reduced activation rate and an altered photobleaching pattern. N55K also showed an altered retinal release from the opsin binding pocket upon light exposure, affecting its optimal functional response. Our data suggest that these sector RP mutations cause different protein phenotypes that may be related to their different clinical progression. Overall, these findings illuminate the molecular mechanisms of sector RP associated with rhodopsin mutations.Two new rhodopsin mutations associated with the rare form sector retinitis pigmentosa (RP) have been found.ResultsCharacterization of both rhodopsin mutant proteins shows different progression correlating with a different behavior of rhodopsin upon light exposure.ConclusionLight plays an important role in triggering sector RP.SignificanceOther mechanisms, in addition to protein misfolding, underlie GPCR dysfunction in pathological processes. Retinitis pigmentosa (RP) is a group of genetically and clinically heterogeneous inherited degenerative retinopathies caused by abnormalities of photoreceptors or retinal pigment epithelium in the retina leading to progressive sight loss. Rhodopsin is the prototypical G-protein-coupled receptor located in the vertebrate retina and is responsible for dim light vision. Here, novel M39R and N55K variants were identified as causing an intriguing sector phenotype of RP in affected patients, with selective degeneration in the inferior retina. To gain insights into the molecular aspects associated with this sector RP phenotype, whose molecular mechanism remains elusive, the mutations were constructed by site-directed mutagenesis, expressed in heterologous systems, and studied by biochemical, spectroscopic, and functional assays. M39R and N55K opsins had variable degrees of chromophore regeneration when compared with WT opsin but showed no gross structural misfolding or altered trafficking. M39R showed a faster rate for transducin activation than WT rhodopsin with a faster metarhodopsinII decay, whereas N55K presented a reduced activation rate and an altered photobleaching pattern. N55K also showed an altered retinal release from the opsin binding pocket upon light exposure, affecting its optimal functional response. Our data suggest that these sector RP mutations cause different protein phenotypes that may be related to their different clinical progression. Overall, these findings illuminate the molecular mechanisms of sector RP associated with rhodopsin mutations.Two new rhodopsin mutations associated with the rare form sector retinitis pigmentosa (RP) have been found. Characterization of both rhodopsin mutant proteins shows different progression correlating with a different behavior of rhodopsin upon light exposure. Light plays an important role in triggering sector RP." @default.
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• W2051283183 date "2014-12-01" @default.
• W2051283183 modified "2023-10-14" @default.
• W2051283183 title "Differential Light-induced Responses in Sectorial Inherited Retinal Degeneration" @default.
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• W2051283183 doi "https://doi.org/10.1074/jbc.m114.609958" @default.
• W2051283183 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/4276860" @default.
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