Cone versus Rod Disease in a Mutant<i>Rpgr</i>Mouse Caused by Different Genetic Backgrounds

Brunner, Sandra; Skosyrski, Sergej; Kirschner-Schwabe, Renate; Knobeloch, Klaus–Peter; Neidhardt, John; Feil, Silke; Glaus, Esther; Luhmann, Ulrich F O; Rüther, Klaus; Berger, Wolfgang

doi:10.1167/iovs.08-2742

Cited by 41 publications

(54 citation statements)

References 48 publications

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“…Mislocalization of rod opsin, short-wavelength (blue) cone opsin, and middle/long-wavelength (red/green) opsin are other early events that suggest that this canine ciliopathy affects all populations of photoreceptors. Similar evidence for altered protein trafficking through the connecting cilium has been reported in murine models (Hong et al 2000(Hong et al , 2005Brunner et al 2010;Wright et al 2011;Thompson et al 2012), and in a carrier patient of XLRP (Adamian et al 2006). Initiation of photoreceptor loss is accompanied by early retinal remodeling events such as rod neurite sprouting, retraction of rod bipolar dendrites, and Müller cell gliosis.…”

Section: Canine Modelssupporting

confidence: 73%

“…The description of the phenotypes of several mouse models of RPGR disease, including XLRP (Hong et al 2000(Hong et al , 2004Brunner et al 2010;Wright et al 2011;Huang et al 2012;Thompson et al 2012) and cone-rod dystrophy (Brunner et al 2010), have been published. Evidence that mice sharing the same RPGR mutation but on a different genetic background can express a different disease phenotype further highlights the potential role of genetic modifiers (Brunner et al 2010).…”

Section: Murine Modelsmentioning

confidence: 99%

“…Evidence that mice sharing the same RPGR mutation but on a different genetic background can express a different disease phenotype further highlights the potential role of genetic modifiers (Brunner et al 2010). Overexpression of the RPGR ex1-19 isoform in photoreceptor cells of transgenic mice leads to early onset (2 months of age) degeneration, whereas no retinal alterations are associated with overexpression of the RPGR ex1-ORF15 isoform ).…”

Section: Murine Modelsmentioning

confidence: 99%

See 2 more Smart Citations

Gene Augmentation for X-Linked Retinitis Pigmentosa Caused by Mutations in RPGR

Beltran

Cideciyan

Lewin

et al. 2014

Cold Spring Harbor Perspectives in Medicine

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Section: Canine Modelssupporting

confidence: 73%

Section: Murine Modelsmentioning

confidence: 99%

Section: Murine Modelsmentioning

confidence: 99%

See 1 more Smart Citation

Gene Augmentation for X-Linked Retinitis Pigmentosa Caused by Mutations in RPGR

Beltran

Cideciyan

Lewin

et al. 2014

Cold Spring Harbor Perspectives in Medicine

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“…[39][40][41] Studies with knockout mice lacking the RPGR gene exhibit cone opsin mislocalization that is evident from early ages onward. 42 For mice in which Rpqr exon 4 was deleted, extent of rod and cone involvement depended on the genetic background with cone disease predomination on the albino BALB/cJ background. 43 From these background, we can draw a conclusion that the distance of 0.5 mm from the fovea have the highest density of cones with lowest density of rods, so that cone cells were easily and primarily affected by RPGR defect.…”

Section: Resultsmentioning

confidence: 99%

Cellular imaging demonstrates genetic mosaicism in heterozygous carriers of an X-linked ciliopathy gene

Hong

et al. 2013

Eur J Hum Genet

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X-linked retinitis pigmentosa (XLRP) is the least common genetic type of retinitis pigmentosa; however, it has extremely devastating consequences to patients' activities of daily living. RPGR and RP2 genes expressed in the photoreceptor sensory cilia are predominantly implicated in XLRP; however, the interpretation of genetic mutations and their correlation with clinical phenotypes remain unknown, and the role of these genes in photoreceptor cilia function is not completely elucidated. Therefore, we evaluated structural characteristics in five female obligate carriers of XLRP by using state-of-the-art non-invasive imaging methods, including adaptive optics (AO) scanning laser ophthalmoscopy (SLO). In all five carriers examined, qualitative and quantitative analyses by AO SLO imaging revealed a mosaic pattern of cone disruption, even in the absence of visual symptoms, normal visual acuity and normal macular thickness, on optical coherence tomography and mildly subnormal full-field cone electroretinographic findings. As the technique is sensitive to the level of a single cone, the ability to visualize the cone cells in vivo should be especially useful in other retinal diseases. In addition, further investigation of XLRP carriers may yield insight into how cone structures change over time and ultimately enable understanding of the role of RPGR and RP2 in cone cell survival. European Journal of Human Genetics (2013Genetics ( ) 21, 1240Genetics ( -1248 doi:10.1038/ejhg.2013; published online 27 February 2013Keywords: X-linked retinitis pigmentosa carrier; photoreceptor layer; adaptive optics scanning laser ophthalmoscopy INTRODUCTIONIdentification of X-linked retinitis pigmentosa (XLRP) carriers is challenging and has serious implications for genetic counseling. Female XLRP carriers usually have normal, or close to normal, visual acuity, but often show some degree of fundus changes, including sectorial or peripheral pigmentary deposits and a tapetal-like reflex (TLR), 1 as well as abnormal fundus. Many previous studies have detailed the prevalence of abnormal fundus photography, 1,2 vitreous fluorophotometry, 3 infrared (IR) reflectance images, 1,2 electroretinographic (ERG), 4,5 psychophysical 6 and flicker-fusion 7 findings in such carriers. More recently, several studies have investigated XLRP carriers with advanced devices, including FAF, 8 multifocal ERG 9 and OCT 10,11 to reveal clinical phenotypes of XLRP. Most XLRP carriers can be identified on the basis of fundus findings and ERG changes; however, 10-30% of carriers show no abnormal ERG or fundus finding. 1,4,5,9 Although XLRP is the least common genetic type of RP, accounting for 6-17% of familial retinitis pigmentosa cases, it is extremely devastating. 1,12,13 In the first or second decade of life, affected individuals experience a decrease in peripheral and night vision, and the disease often leads to partial or complete blindness in the fourth or fifth decade of life. 14 In contrast to the severe retinal degeneration in affected men, female carriers of t...

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“…One of the two main isoforms is the widely expressed RPGR [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19] consisting of 19 exons encoding a protein of 815 amino acids where exons 2-11 comprise the RLD [10]. A carboxy-terminal CAAX box, specific for geranylgeranylation, was shown to be essential for the localization and function of the protein [11].…”

Section: Introductionmentioning

confidence: 99%

The interplay between RPGR, PDEδ and Arl2/3 regulate the ciliary targeting of farnesylated cargo

et al. 2013

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Defects in primary cilia result in human diseases known as ciliopathies. The retinitis pigmentosa GTPase regulator (RPGR), mutated in the most severe form of the eye disease, is located at the transition zone of the ciliary organelle. The RPGR-interacting partner PDEd is involved in trafficking of farnesylated ciliary cargo, but the significance of this interaction is unknown. The crystal structure of the propeller domain of RPGR shows the location of patient mutations and how they perturb the structure. The RPGR . PDEd complex structure shows PDEd on a highly conserved surface patch of RPGR. Biochemical experiments and structural considerations show that RPGR can bind with high affinity to cargo-loaded PDEd and exposes the Arl2/Arl3-binding site on PDEd. On the basis of these results, we propose a model where RPGR is acting as a scaffold protein recruiting cargo-loaded PDEd and Arl3 to release lipidated cargo into cilia.

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Cone versus Rod Disease in a MutantRpgrMouse Caused by Different Genetic Backgrounds

Abstract: Both Rpgr mutant mouse lines developed retinal disease with a striking effect of the genetic background. Cone-specific modifiers might influence the retinal phenotype in the BALB/c strain. The two lines provide models to study RPGR function in rods and cones, respectively.

Cited by 41 publications

References 48 publications

Gene Augmentation for X-Linked Retinitis Pigmentosa Caused by Mutations in RPGR

Gene Augmentation for X-Linked Retinitis Pigmentosa Caused by Mutations in RPGR

Cellular imaging demonstrates genetic mosaicism in heterozygous carriers of an X-linked ciliopathy gene

The interplay between RPGR, PDEδ and Arl2/3 regulate the ciliary targeting of farnesylated cargo

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