Mutational Analysis of the<i>Rhodopsin</i>Gene in Sector Retinitis Pigmentosa

Napier, Maria; Durga, Dash; Wolsley, Clive; Chamney, Sarah; Alexander, Sharon; Brennan, Rosie; Simpson, David; Silvestri, G; Willoughby, Colin E.

doi:10.3109/13816810.2014.958862

Cited by 13 publications

(9 citation statements)

References 28 publications

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“…I130 3×43 N/F likely loosens/stabilizes the hydrophobic lock, weakens/strengthens the TM3-TM6 packing and leads to constitutively active/inactive receptors. Another example is T58 1×53 M in rhodopsin, which was reported as a loss-of-function mutation that causes retinitis pigmentosa 4 42 . T58 1×53 M likely increases hydrophobic contacts with Y306 7×53 and P303 7×50 , which retards the inward movement of TM7 towards TM3 and eventually decreases G protein recruitment.…”

Section: Resultsmentioning

confidence: 99%

Universal activation mechanism of class A GPCRs

Zhou

Yang

et al. 2019

Preprint

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19Class A G protein-coupled receptors (GPCRs) influence virtually every aspect of human physiology. 20 GPCR activation is an allosteric process that links agonist binding to G protein recruitment, with the 21 hallmark outward movement of transmembrane helix 6 (TM6). However, what leads to TM6 22 movement and the key residue-level changes of this trigger remain less well understood. Here, by 23 analyzing over 230 high-resolution structures of class A GPCRs, we discovered a modular, universal 24 GPCR activation pathway that unites previous findings into a common activation mechanism, directly 25 linking the bottom of ligand-binding pocket with G protein-coupling region. We suggest that the 26 modular nature of the universal GPCR activation pathway allowed for the decoupling of the evolution 27 of the ligand binding site, G protein binding region and the residues important for receptor activation. 28 Such an architecture might have facilitated GPCRs to emerge as a highly successful family of proteins 29 for signal transduction in nature. 30

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Section: Resultsmentioning

confidence: 99%

Universal activation mechanism of class A GPCRs

Zhou

Yang

et al. 2019

Preprint

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“…A sector pattern of photoreceptor loss has been described in dominant RP caused by a variety of missense mutations in the rhodopsin gene. 1,2,[24][25][26][27][28][29][30] These mutations, which appear to confer a light-sensitive degenerative phenotype, are those associated with misfolding and endoplasmic reticulum (ER) retention, and those with altered posttranslational modification and reduced stability of the protein. 5,31 Potential mechanisms by which light might act as a modifying factor include depletion of free 11-cis-retinal, which in low-luminance conditions may act as a molecular chaperone for rhodopsin, 8,14,15 direct destabilization of the mutant protein within the rod outer segment, 2,32,33 and via activation of the phototransduction cascade.…”

Section: Discussionmentioning

confidence: 99%

Filtration of Short-Wavelength Light Provides Therapeutic Benefit in Retinitis Pigmentosa Caused by a Common Rhodopsin Mutation

Orlans

Merrill

Barnard

et al. 2019

Invest. Ophthalmol. Vis. Sci.

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“…It encodes a 348-amino acid rod-specific protein rhodopsin which is a typical seven TM G-protein-coupled receptor [22]. When rhodopsin absorbs the photon, the retinal chromophore (11- cis -retinal) changes to an all-trans-retinal, leads to a phototransduction cascade activation, which plays an important role in vision [11,23].…”

Section: Discussionmentioning

confidence: 99%

“…Sector RP is characterized by adult onset and regionalized or sectorial retinal dysfunction [11]. At least 13 RHO gene mutations associate with sector RP [11,23,33–35].…”

Section: Discussionmentioning

confidence: 99%

Heterozygous RHO p.R135W missense mutation in a large Han-Chinese family with retinitis pigmentosa and different refractive errors

Guo

et al. 2019

Bioscience Reports

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Retinitis pigmentosa (RP), the most common type of inherited retinal degeneration causing blindness, initially manifests as severely impaired rod function followed by deteriorating cone function. Mutations in the rhodopsin gene (RHO) are the most common cause of autosomal dominant RP (adRP). The present study aims to identify the disease-causing mutation in a numerous, four-generation Han-Chinese family with adRP detected by whole exome sequencing and Sanger sequencing. Afflicted family members present classic adRP along with heterogeneous clinical phenotypes including differing refractive errors, cataracts, astigmatism and epiretinal membranes. A missense mutation, c.403C>T (p.R135W), in the RHO gene was identified in nine subjects and it co-segregated with family members. The mutation is predicted to be disease-causing and results in rhodopsin protein abnormalities. The present study extends the genotype–phenotype relationship between RHO gene mutations and adRP clinical findings. The results have implications for familial genetic counseling, clinical management and developing RP target gene therapy strategies.

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Mutational Analysis of theRhodopsinGene in Sector Retinitis Pigmentosa

Cited by 13 publications

References 28 publications

Universal activation mechanism of class A GPCRs

Universal activation mechanism of class A GPCRs

Filtration of Short-Wavelength Light Provides Therapeutic Benefit in Retinitis Pigmentosa Caused by a Common Rhodopsin Mutation

Heterozygous RHO p.R135W missense mutation in a large Han-Chinese family with retinitis pigmentosa and different refractive errors

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