Leber Congenital Amaurosis

Perrault, Isabelle; Rozet, Jean–Michel; Gerber, Sylvie; Ghazi, Imad; Leowski, Corinne; Ducroq, Dominique; Souied, Eric H.; Dufier, Jean‐Louis; Münnich, Arnold; Kaplan, Josseline

doi:10.1006/mgme.1999.2906

Cited by 147 publications

(100 citation statements)

References 39 publications

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“…1,15 The genetic heterogeneity of LCA might affect the disease phenotype and lead to different clinical presentations. In the series of Perrault et al, 16 GUCY2D, RPE65, and CRX genes accounted for 27% of Leber cases. Hanein et al, 9 screened seven LCA causative genes in 179 unrelated LCA cases and found mutations in 47.5% of the patients (GUCY2D (21.2%), CRB1 (10%), RPE65 (6.1%), RPGRIP1 (4.5%), AIPL1 (3.4%), TULP1 (1.7%), and CRX (0.6%)).…”

Section: Discussionmentioning

confidence: 90%

“…4 Mutations in GUCY2D and RPE65 genes are associated with normal fundus findings at birth, followed by salt and pepper appearance with varying functional outcomes. 16 In this report, we described the clinical features of a Turkish family with macular coloboma-type LCA. The genetic analysis showed a lack of linkage to LCA5 locus in contrast to a report by Mohamed et al 13 The affected individuals from both families presented with bilateral macular atrophy and perifoveal pigmentary changes.…”

Section: Discussionmentioning

confidence: 97%

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Exclusion of LCA5 locus in a consanguineous Turkish family with macular coloboma-type LCA

Özgül

Bozkurt²,

Kıratlı

et al. 2005

Eye

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Background Leber's congenital amaurosis (LCA) is an inherited retinal dystrophy, which causes severe visual impairment in early childhood. Recent molecular genetic studies have linked 11 loci (AIPL1, CRB1, CRX, GUCY2D, RPE65, RDH12, RPGRIP1, TULP1, LCA3, LCA5, and LCA9) to LCA. LCA5 is a new locus, which maps to the 6q11-q16 chromosomal region and was found to be associated with macular coloboma-type LCA in a Pakistani family. Herein, we describe the molecular genetic features of a consanguineous Turkish family in which four children have macular colobomatype LCA. Methods Haplotype analysis was performed on the DNA of the family members using microsatellite markers against GUCY2D, RPE65, and LCA5. Genomic DNA was screened for mutations by means of singlestrand conformational polymorphism (SSCP) analysis in exons of the RPE65 and CRX genes. Results In haplotype analysis, no linkage to LCA5 or GUCY2D loci was detected. None of the tested markers showed homozygosity or segregation between affected siblings. PCR-SSCP mutation analysis revealed no mutations in the screened RPE65 and CRX genes. Conclusion We excluded LCA5 as the genetic cause of macular coloboma-type LCA in this Turkish family. Macular coloboma-type LCA shows genetic heterogeneity and it is not possible to establish a phenotype-genotype correlation with LCA5 and macular coloboma.

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Section: Discussionmentioning

confidence: 90%

Section: Discussionmentioning

confidence: 97%

Exclusion of LCA5 locus in a consanguineous Turkish family with macular coloboma-type LCA

Özgül

Bozkurt²,

Kıratlı

et al. 2005

Eye

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“…LCA1 patients present in infancy with severely impaired vision and extinguished ERG despite a normal fundus and retained photoreceptors in both their macular and peripheral retina for decades. [39][40][41][42] There is relatively better maintenance of retinal structure in LCA1 patients than that seen in other forms of the disease. 42 Taken together, this suggests an important role for the zebrafish as an animal model on which rapid visual screening and retinal histology may offer a unique advantage in the study of GC1 disease through both gene knockdown or future studies of dominant gene supplementation.…”

Section: Discussionmentioning

confidence: 97%

Gucy2f zebrafish knockdown – a model for Gucy2d-related leber congenital amaurosis

et al. 2012

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Mutations in retinal-specific guanylate cyclase (Gucy2d) are associated with Leber congenital amaurosis-1 (LCA1). Zebrafish offer unique advantages relative to rodents, including their excellent color vision, precocious retinal development, robust visual testing strategies, low cost, relatively easy transgenesis and shortened experimental times. In this study we will demonstrate the feasibility of using gene-targeting in the zebrafish as a model for the photoreceptor-specific GUCY2D-related LCA1, by reporting the visual phenotype and retinal histology resulting from Gucy2f knockdown. Gucy2f zebrafish LCA-orthologous cDNA was identified and isolated by PCR amplification. Its expression pattern was determined by whole-mount in-situ hybridization and its function was studied by gene knockdown using two different morpholino-modified oligos (MO), one that blocks translation of Gucy2f and one that blocks splicing of Gucy2f. Visual function was assessed with an optomotor assay on 6-days-postfertilization larvae, and by analyzing changes in retinal histology. Gucy2f knockdown resulted in significantly lower vision as measured by the optomotor response compared with uninjected and control MO-injected zebrafish larvae. Histological changes in the Gucy2f-knockdown larvae included loss and shortening of cone and rod outer segments. A zebrafish model of Gucy2f-related LCA1 displays early visual dysfunction and photoreceptor layer dystrophy. This study serves as proof of concept for the use of zebrafish as a simple, inexpensive model with excellent vision on which further study of LCA-related genes is possible. Keywords: leber congenital amaurosis; animal model; GUCY2D; optomotor assay INTRODUCTION Leber congenital amaurosis (LCA) is a family of severe, early-onset, autosomal-recessive forms of pediatric blindness. LCA has been linked to more than 16 genes, often exhibiting clinical heterogeneity. 1,2 LCA1 is caused by mutations in the gene GUCY2D, which encodes the retinal Gucy2d-1 (GC1) and accounts for B20% of all cases of LCA. 3 LCA2 is caused by mutations in the RPE65 gene, which is expressed in the retinal pigment epithelium. Breakthrough research has demonstrated visual improvement following gene therapy trials in humans with LCA2. 4,5 Human trials relied on a decade of proof-of-concept studies in canine and rodent models. 6-8 Unlike LCA2, in which gene therapy is aimed at correcting an RPE defect, searching for gene therapy for LCA1 will involve an attempt at treating the photoreceptors. European Journal of Human GeneticsResearch in inherited retinal disease relies heavily on animal models, commonly mammals such as mice and dogs. These animal models have significant advantages, including the availability of knockout technology. Two specific drawbacks slow the applicability of rodent or canine models for study of relatively rare genetic diseases such as LCA and other retinal dystrophies. The first difficulty is the high cost and length of time required to create a new knockout line; thus, it is applicable only for comm...

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“…Photoreceptors are packed into a single layer of cells (the outer nuclear layer, ONL) with specific geometric arrangements (Raymond, 1995). How the ONL maintains its integrity has been attracting increasing attention lately because a number of blinding human retinal diseases, such as Retinitis Pigmentosa and Leber Congenital Amaurosis, directly affect the stability of this retinal layer (Rivolta et al, 2002;Perrault et al, 1999). The packing of photoreceptors into a single cellular layer requires precise coordination of photoreceptor adhesion.…”

Section: Introductionmentioning

confidence: 99%

Nok plays an essential role in maintaining the integrity of the outer nuclear layer in the zebrafish retina

Wei

Zou

Takechi

et al. 2006

Experimental Eye Research

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Proper visual function of the vertebrate retina requires the maintenance of the integrity of the retinal outer nuclear layer (ONL), which is often affected in many blinding human retinal diseases.While the structural integrity of the ONL has long been considered to be maintained primarily through the outer limiting membrane (OLM), we have little knowledge on the development and maintenance of the OLM itself. Here, by analyzing the adhering properties of photoreceptors in zebrafish N-cad and nok mutants, we demonstrated for the first time that the nok gene is essential for the establishment and/or maintenance of the OLM. In addition, our results imply the possibility that Nok, Crumbs, and their associated proteins may constitute a type of photoreceptor-photoreceptor junctional complex that has not been described before. Thus, our study provides novel insights into the mechanisms by which the integrity of the ONL is maintained in the vertebrate retina.

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Leber Congenital Amaurosis

Cited by 147 publications

References 39 publications

Exclusion of LCA5 locus in a consanguineous Turkish family with macular coloboma-type LCA

Exclusion of LCA5 locus in a consanguineous Turkish family with macular coloboma-type LCA

Gucy2f zebrafish knockdown – a model for Gucy2d-related leber congenital amaurosis

Nok plays an essential role in maintaining the integrity of the outer nuclear layer in the zebrafish retina

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