Spectrum of retGC1 mutations in Leber's congenital amaurosis

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

doi:10.1038/sj.ejhg.5200503

Cited by 98 publications

(75 citation statements)

References 17 publications

(21 reference statements)

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“…3 Dominant mutations in GC1 are also a major cause of cone-rod (including CORD6) and cone dystrophies, accounting for up to 35% of such cases. [35][36][37][38] LCA1 is part of a family of severe, early-onset, autosomal recessive blinding disorders characterized by extinguished electroretinogram, which precedes photoreceptor degeneration.…”

Section: Discussionmentioning

confidence: 99%

“…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.…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2012

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“…33 Early-onset visual impairment and nystagmus were also observed in patient 71 carrying GUCY2D variants who showed no ERG responses at the age of 1 year. 34,35 Patients carrying two RPE65 variants presented with symptoms of nystagmus, lack of fixation, night blindness and/or orientation difficulties within the first year of age, except one patient who according to the anamnesis presented with visual impairment at 2 years of age. All patients showed extinct ERG responses and suffered from nystagmus and severe night blindness.…”

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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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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“…20,21 Those missense mutations were all shown to be null alleles that dramatically impaired the catalytic activity and thus led to a severe phenotype, similar to the ones caused by truncating mutations that almost make up half of all GUCY2D mutations. 7,17 In all, 12% of all LCA types 8 and up to 40% of dominant CORD 6 are caused by defects in GUCY2D, an important component in the recovery process of phototransduction in the vertebrate retina. Almost all CORD6 mutations (all with dominant effect) are confined to three consecutive codons in exon 13 encoding part of the dimerization domain of retGC.…”

Section: Discussionmentioning

confidence: 99%

“…Whole genome linkage analysis and fine mapping studies identified the sole homozygosity region on chromosome 17p13.3. GUCY2D, residing in this region, was selected as a strong candidate gene, because GUCY2D mutations have been reported as a frequent cause for both autosomal dominant CORD 5,6 (CORD6 (MIM 601777)) and Leber's congenital amaurosis 7,8 (LCA1 (MIM 204000)), which is typically a recessive condition. Indeed, we identified a novel recessive GUCY2D mutation in the family.…”

Section: Introductionmentioning

confidence: 99%

A novel recessive GUCY2D mutation causing cone–rod dystrophy and not Leber's congenital amaurosis

2010

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Cone-rod dystrophies are inherited retinal dystrophies that are characterized by progressive degeneration of cones and rods, causing an early decrease in central visual acuity and colour vision defects, followed by loss of peripheral vision in adolescence or early adult life. Both genetic and clinical heterogeneity are well known. In a family with autosomal recessive cone-rod dystrophy, genetic analyses comprising genome scan with microsatellite markers, fine mapping and candidate gene approach resulted in the identification of a homozygous missense GUCY2D mutation. This is the first GUCY2D mutation associated with autosomal recessive cone-rod dystrophy rather than Leber's congenital amaurosis (LCA), a severe disease leading to childhood blindness. This study hence establishes GUCY2D, which is a common cause for both recessive LCA and dominant cone-rod dystrophy, as a good candidate for autosomal recessive cone-rod dystrophy.

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Spectrum of retGC1 mutations in Leber's congenital amaurosis

Cited by 98 publications

References 17 publications

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

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

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

A novel recessive GUCY2D mutation causing cone–rod dystrophy and not Leber's congenital amaurosis

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