Mice with a D190N Mutation in the Gene Encoding Rhodopsin: A Model for Human Autosomal-Dominant Retinitis Pigmentosa

Sancho‐Pelluz, Javier; Tosi, Joaquin; Hsu, Chun‐Wei; Lee, Frances; Wolpert, Kyle; Tabacaru, Mirela; Greenberg, Jay; Tsang, Stephen H.; Lin, Chyuan‐Sheng

doi:10.2119/molmed.2011.00475

Cited by 18 publications

(20 citation statements)

References 25 publications

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“…of D190N ( Figure 4A). D190N had previously been shown to be a less severe RP-linked mutation (Fishman et al 1992;Tsui et al 2008;Liu et al 2013), and ERG data from patients matches our observation that this missense mutation does not completely disrupt rhodopsin function (Sancho-Pelluz et al 2012). The G89D and L125R mutations also had a reduced but measurable response to light when expressed in yeast, which fits with previous trends observed ( Bosch et al 2003).…”

Section: Magnitude Of Light-activated Signal Transduction In Yeast Cosupporting

confidence: 90%

Coupling of Human Rhodopsin to a Yeast Signaling Pathway Enables Characterization of Mutations Associated with Retinal Disease

et al. 2018

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G protein-coupled receptors (GPCRs) are crucial sensors of extracellular signals in eukaryotes, with multiple GPCR mutations linked to human diseases. With the growing number of sequenced human genomes, determining the pathogenicity of a mutation is challenging, but can be aided by a direct measurement of GPCR-mediated signaling. This is particularly difficult for the visual pigment rhodopsin-a GPCR activated by light-for which hundreds of mutations have been linked to inherited degenerative retinal diseases such as retinitis pigmentosa. In this study, we successfully engineered, for the first time, activation by human rhodopsin of the yeast mating pathway, resulting in signaling via a fluorescent reporter. We combine this novel assay for rhodopsin lightdependent activation with studies of subcellular localization, and the upregulation of the unfolded protein response in response to misfolded rhodopsin protein. We use these assays to characterize a panel of rhodopsin mutations with known molecular phenotypes, finding that rhodopsin maintains a similar molecular phenotype in yeast, with some interesting differences. Furthermore, we compare our assays in yeast with clinical phenotypes from patients with novel disease-linked mutations. We demonstrate that our engineered yeast strain can be useful in rhodopsin mutant classification, and in helping to determine the molecular mechanisms underlying their pathogenicity. This approach may also be applied to better understand the clinical relevance of other human GPCR mutations, furthering the use of yeast as a tool for investigating molecular mechanisms relevant to human disease.

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Section: Magnitude Of Light-activated Signal Transduction In Yeast Cosupporting

confidence: 90%

Coupling of Human Rhodopsin to a Yeast Signaling Pathway Enables Characterization of Mutations Associated with Retinal Disease

et al. 2018

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“…Such differences could give rise to immediate structural consequences affecting the high affinity calcium EF-hand binding motif in the GCAP1 protein. Different amino acid substitutions at the same position can result in phenotypically different degrees of severity in functional retinal impairment, as also seen in dominant retinitis pigmentosa [27]. …”

Section: Discussionmentioning

confidence: 99%

Disease progression in autosomal dominant cone–rod dystrophy caused by a novel mutation (D100G) in the GUCA1A gene

et al. 2013

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Purpose To document longitudinal fundus autofluorescence (FAF) and electroretinogram (ERG) findings in a family with cone-rod dystrophy (CRD) caused by a novel missense mutation (D100G) in the GUCA1A gene. Methods Observational case series. Results Three family members 26 to 49 years old underwent complete clinical examinations. In all patients, funduscopic findings showed intraretinal pigment migration, loss of neurosensory retinal pigment epithelium (RPE), and macular atrophy. Fundus autofluorescence (FAF) imaging revealed the presence of a progressive hyperautofluorescent ring around a hypoautofluorescent center corresponding to macular atrophy. Full-field electroretinograms (ERG) showed a more severe loss of cone than rod function in each patient. 30 Hz flicker responses fell far below normal limits. Longitudinal FAF and ERG findings in one patient suggested progressive cone-rod dystrophy. Two more advanced patients exhibited reduced rod response consistent with disease stage. Direct sequencing of the GUCA1A gene revealed a new missense mutation, p.Asp100Gly (D100G), in each patient. Conclusion Patients with autosomal dominant CRD caused by a D100G mutation in GUCA1A exhibit progressive vision loss early within the first decade of life identifiable by distinct ERG characteristics and subsequent genetic testing.

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“…Both S186W and D190N mutants can fold properly, bind 11- cis retinal, and exhibit spectral properties indistinguishable from wild-type rhodopsin (Janz & Farrens, 2003; Liu et al, 2013). Patients and knockin mice that express the D190N mutant have desensitized rod photoreceptor cells (Sancho-Pelluz et al, 2012), an expected outcome for cells expressing a constitutively active mutant. In contrast to constitutively active mutants causing CNB, the D190N mutant does not exhibit solvent accessibility in its chromophore-binding pocket in the dark state (Janz & Farrens, 2003), which indicates that the mutation itself does not promote an active state via changes to protein structure like in CNB-causing mutants.…”

Section: Constitutive Activty In Rhodopsin That Causes Diseasementioning

confidence: 99%

“…All classes of constitutively active mutants discussed are able to activate the phototransduction cascade in the absence of light and thereby desensitize rod photoreceptor cells (Chen et al, 2006; Sancho-Pelluz et al, 2012; Sieving et al, 1995). While this light-independent activity underlies the observed pathology in a variety of retinal diseases, different constitutively active mutants can promote different physiological outcomes.…”

Section: How Constitutive Activity Can Cause Different Phenotypesmentioning

confidence: 99%

Constitutively Active Rhodopsin and Retinal Disease

Park

2014

Advances in Pharmacology

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Rhodopsin is the light receptor in rod photoreceptor cells of the retina that initiates scotopic vision. In the dark, rhodopsin is bound to the chromophore 11-cis retinal, which locks the receptor in an inactive state. The maintenance of an inactive rhodopsin in the dark is critical for rod photoreceptor cells to remain highly sensitive. Perturbations by mutation or absence of 11-cis retinal can cause rhodopsin to become constitutively active, which leads to the desensitization of photoreceptor cells and, in some instances, retinal degeneration. Constitutive activity can arise in rhodopsin by various mechanisms and can cause a variety of inherited retinal diseases including Leber congenital amaurosis, congenital night blindness, and retinitis pigmentosa. In this review, the molecular and structural properties of different constitutively active forms of rhodopsin are overviewed and the possibility that constitutive activity can arise from different active-state conformations is discussed.

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Mice with a D190N Mutation in the Gene Encoding Rhodopsin: A Model for Human Autosomal-Dominant Retinitis Pigmentosa

Abstract: Rhodopsin is the G protein-coupled receptor in charge of initiating signal transduction in rod photoreceptor cells upon the arrival of the photon. D190N (Rho D190n ), a missense mutation in rhodopsin, causes autosomal-dominant retinitis pigmentosa

Cited by 18 publications

References 25 publications

Coupling of Human Rhodopsin to a Yeast Signaling Pathway Enables Characterization of Mutations Associated with Retinal Disease

Coupling of Human Rhodopsin to a Yeast Signaling Pathway Enables Characterization of Mutations Associated with Retinal Disease

Disease progression in autosomal dominant cone–rod dystrophy caused by a novel mutation (D100G) in the GUCA1A gene

Constitutively Active Rhodopsin and Retinal Disease

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