Clinical Course and Visual Function in a Family With Mutations in the RPE65 Gene

Felius, Joost; Thompson, Debra A.; Khan, Naheed W.; Bingham, Eve L.; Jamison, Jeffrey Adam; Kemp, Jennifer; Sieving, Paul A.

doi:10.1001/archopht.120.1.55

Cited by 45 publications

(44 citation statements)

References 27 publications

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“…An equally high frequency of 36 In five individuals with LCA (F1, F5, F14, F28, F59), one heterozygous variant was identified upon sequence analysis of the entire coding regions of the corresponding genes. The GUCY2D variant p.(R838P) has been reported in previous LCA studies as an autosomal dominant mutation.…”

Section: Discussionmentioning

confidence: 99%

“…Similar phenotype data were described for individuals with RPE65 variants in several previous studies. 36,37 RPE65 LOVD variant depositions Novel and previously described variants identified in this study have been listed in the respective LOVD for the mutated genes. [38][39][40][41][42][43] In addition, we collected all RPE65 variants that were published up to 2014.…”

Section: Clinical Findingsmentioning

confidence: 99%

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Comprehensive genotyping reveals RPE65 as the most frequently mutated gene in Leber congenital amaurosis in Denmark

et al. 2015

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Leber congenital amaurosis (LCA) represents the most severe form of inherited retinal dystrophies with an onset during the first year of life. Currently, 21 genes are known to be associated with LCA and recurrent mutations have been observed in AIPL1, CEP290, CRB1 and GUCY2D. In addition, sequence analysis of LRAT and RPE65 may be important in view of treatments that are emerging for patients carrying variants in these genes. Screening of the aforementioned variants and genes was performed in 64 Danish LCA probands. Upon the identification of heterozygous variants, Sanger sequencing was performed of the relevant genes to identify the second allele. In combination with prior arrayed primer extension analysis, this led to the identification of two variants in 42 of 86 cases (49%). Remarkably, biallelic RPE65 variants were identified in 16% of the cases, and one novel variant, p.(D110G), was found in seven RPE65 alleles. We also collected all previously published RPE65 variants, identified in 914 alleles of 539 patients with LCA or early-onset retinitis pigmentosa, and deposited them in the RPE65 Leiden Open Variation Database (LOVD). The in silico pathogenicity assessment of the missense and noncanonical splice site variants, as well as an analysis of their frequency in~60 000 control individuals, rendered 864 of the alleles to affect function or probably affect function. This comprehensive database can now be used to select patients eligible for gene augmentation or retinoid supplementation therapies.

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Section: Discussionmentioning

confidence: 99%

Section: Clinical Findingsmentioning

confidence: 99%

Comprehensive genotyping reveals RPE65 as the most frequently mutated gene in Leber congenital amaurosis in Denmark

et al. 2015

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“…This proposal is supported by the findings that RPE65 is predominately expressed in RPE and not in Müller cells. The absence of cone function in Rpe65 −/− mouse models and in human patients with RPE65 mutations (Felius, et al 2002) strongly suggest that the retinoid cycle as described for the cone dominated retinas of chicken and squirrel is not applicable to the cone retinoid recycling in the rod dominated retina.…”

Section: Discussionmentioning

confidence: 99%

Retinoid processing in cone and Müller cell lines

Kanan

Kasus‐Jacobi

Moiseyev

et al. 2008

Experimental Eye Research

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To determine whether cones and Müller cells in the rod dominated retina, cooperate to regenerate the 11-cis retinal chromophore via the retinoid cycle, two cell lines from the rod dominated retinas of Murine were used for this study, 661W a mouse cell line derived from cones and rMC-1, a rat Müller cell line. Retinoid cycle enzymes were analyzed by RT-PCR and their catalytic activity were detected by incubation with retinoids and analyzed by HPLC. We found that, 661W cells are capable of reducing all-trans retinal to all-trans retinol due to the presence of multiple dehydrogenases and generate minor amounts of retinyl-ester. The rMC-1 cells take up all-trans retinol and oxidizes it to all-trans retinal or esterify it to retinyl-ester, but are incapable of isomerizing all-trans retinoids to 11-cis retinoids. This could be a reflection of lack of necessary activities in Müller cells in vivo which suggests that Müller cells do not contribute to retinoid cycling by regenerating 11-cis retinoids. Alternatively, this could be due to the potential that rMC-1, as a transformed cell line, has stopped expressing the proteins needed for the regeneration of 11-cis retinoids.

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“…It is therefore essential for the formation of rhodopsin, and animals without it are almost completely incapable of producing normal visual pigment. Mutations in the Rpe65 gene are thought to be responsible for several human retinal degenerations, including Lebers congenital amaurosis, (36,39) autosomal recessive retinitis pigmentosa (38) and rod-cone dystrophy. (40) In Rpe65 À/À mice kept in normal room light (12 hours on and 12 hours off), the outer segments of the rods have very little rhodopsin but abundant opsin.…”

Section: Continuous Light Kills By Activating Transductionmentioning

confidence: 99%

Why photoreceptors die (and why they don't)

Fain

2006

BioEssays

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Light can kill the photoreceptors of the eye, not only very bright direct sunlight, but more moderate illumination if the light is present continuously. Recent experiments show that rod apoptosis can be triggered by strong and constant activation of transduction, and that death can be prevented if transduction is inhibited even though the eye is illuminated. Vitamin A deficiency and genetically inherited diseases, such as some forms of retinitis pigmentosa and Leber congenital amaurosis, appear to kill like this: transduction is activated at a high rate and continuously, and this causes the rods to die. Why does transduction kill? Our best guess is that continuous activation produces a prolonged lowering of the Ca2+ concentration, which is also thought to kill neurons in tissue culture and during the development of the nervous system. To prevent death in constant light, rods have evolved protective mechanisms including modulation of channels and ion transport to keep the Ca2+ from going too low. Prolonged light exposure also causes migration of transduction proteins from one part of the cell to another and a reversible shortening of the rod outer segments, the part of the cell that contains the pigment rhodopsin. All of these mechanisms are at work in the normal eye to reduce transduction and prevent the Ca2+ concentration from dropping too low for too long a time. That most of us retain our vision our entire lives is a testament to their effectiveness. BioEssays 28: 344–354, 2006. © 2006 Wiley Periodicals, Inc.

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Clinical Course and Visual Function in a Family With Mutations in the RPE65 Gene

Cited by 45 publications

References 27 publications

Comprehensive genotyping reveals RPE65 as the most frequently mutated gene in Leber congenital amaurosis in Denmark

Comprehensive genotyping reveals RPE65 as the most frequently mutated gene in Leber congenital amaurosis in Denmark

Retinoid processing in cone and Müller cell lines

Why photoreceptors die (and why they don't)

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