CRB1 Gene Mutation Causing Different Phenotypes of Leber Congenital Amaurosis in Siblings

Khan, Shaheryar Ahmed; Nestel, A R

doi:10.18502/jovr.v14i4.5467

Cited by 6 publications

(3 citation statements)

References 13 publications

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“…The unique fundus picture in RDH12 mutation is it's watercolour like appearance, where there is a clear demarcation pattern at the boundary between the preserved and affected retina, which enlarges with the advancement of disease and becomes less apparent at the end stage of the dystrophy. 40 There is loss of macular autofluorescence and typical peripapillary sparing is clearly evident on autofluorescence. Spectral domain OCT shows loss of normal foveal architecture and macular thinning.…”

Section: Exploring Gene Targets In Lcamentioning

confidence: 98%

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<p>Voretigene Neparvovec and Gene Therapy for Leber’s Congenital Amaurosis: Review of Evidence to Date</p>

Padhy¹,

Takkar²,

Narayanan³

et al. 2020

TACG

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Gene therapy has now evolved as the upcoming modality for management of many disorders, both inheritable and non-inheritable. Knowledge of genetics pertaining to a disease has therefore become paramount for physicians across most specialities. Inheritable retinal dystrophies (IRDs) are notorious for progressive and relentless vision loss, frequently culminating in complete blindness in both eyes. Leber's congenital amaurosis (LCA) is a typical example of an IRD that manifests very early in childhood. Research in gene therapy has led to the development and approval of voretigene neparvovec (VN) for use in patients of LCA with a deficient biallelic RPE65 gene. The procedure involves delivery of a recombinant virus vector that carries the RPE65 gene in the subretinal space. This comprehensive review reports the evidence thus far in support of gene therapy for LCA. We explore and compare the various gene targets including but not limited to RPE65, and discuss the choice of vector and method for ocular delivery. The review details the evolution of gene therapy with VN in a phased manner, concluding with the challenges that lie ahead for its translation for use in communities that differ much both genetically and economically.

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Section: Exploring Gene Targets In Lcamentioning

confidence: 98%

“…The Application of Clinical Genetics 2020:13 194 all cases), and some other IRDs. [38][39][40] CRB1 is implicated in cellular adhesion, maintenance of apico-basal polarization, and cellular communication. It is considered critical for the structure and function of photoreceptors.…”

Section: Dovepressmentioning

confidence: 99%

<p>Voretigene Neparvovec and Gene Therapy for Leber’s Congenital Amaurosis: Review of Evidence to Date</p>

Padhy¹,

Takkar²,

Narayanan³

et al. 2020

TACG

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“…For example, mutations in genes encoding proteins that may directly or indirectly interact with CRB1 could potentially mediate different pathogenic effects. In support of this hypothesis, distinct and variable disease phenotypes have been observed among individuals with identical CRB1 alleles, suggesting the existence of genetic modifiers [ 2 – 4 , 6 , 7 , 27 – 29 ]. Additionally, in about 30% of affected individuals only a single CRB1 variant allele has been detected suggesting that other genetic variants, possibly including modifier loci, may contribute to the disease [ 2 ].…”

Section: Introductionmentioning

confidence: 93%

Identification of Arhgef12 and Prkci as genetic modifiers of retinal dysplasia in the Crb1rd8 mouse model

et al. 2022

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Mutations in the apicobasal polarity gene CRB1 lead to diverse retinal diseases, such as Leber congenital amaurosis, cone-rod dystrophy, retinitis pigmentosa (with and without Coats-like vasculopathy), foveal retinoschisis, macular dystrophy, and pigmented paravenous chorioretinal atrophy. Limited correlation between disease phenotypes and CRB1 alleles, and evidence that patients sharing the same alleles often present with different disease features, suggest that genetic modifiers contribute to clinical variation. Similarly, the retinal phenotype of mice bearing the Crb1 retinal degeneration 8 (rd8) allele varies with genetic background. Here, we initiated a sensitized chemical mutagenesis screen in B6.Cg-Crb1rd8/Pjn, a strain with a mild clinical presentation, to identify genetic modifiers that cause a more severe disease phenotype. Two models from this screen, Tvrm266 and Tvrm323, exhibited increased retinal dysplasia. Genetic mapping with high-throughput exome and candidate-gene sequencing identified causative mutations in Arhgef12 and Prkci, respectively. Epistasis analysis of both strains indicated that the increased dysplastic phenotype required homozygosity of the Crb1rd8 allele. Retinal dysplastic lesions in Tvrm266 mice were smaller and caused less photoreceptor degeneration than those in Tvrm323 mice, which developed an early, large diffuse lesion phenotype. At one month of age, Müller glia and microglia mislocalization at dysplastic lesions in both modifier strains was similar to that in B6.Cg-Crb1rd8/Pjn mice but photoreceptor cell mislocalization was more extensive. External limiting membrane disruption was comparable in Tvrm266 and B6.Cg-Crb1rd8/Pjn mice but milder in Tvrm323 mice. Immunohistological analysis of mice at postnatal day 0 indicated a normal distribution of mitotic cells in Tvrm266 and Tvrm323 mice, suggesting normal early development. Aberrant electroretinography responses were observed in both models but functional decline was significant only in Tvrm323 mice. These results identify Arhgef12 and Prkci as modifier genes that differentially shape Crb1-associated retinal disease, which may be relevant to understanding clinical variability and underlying disease mechanisms in humans.

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CRB1-related retinopathy overlapping the ocular phenotype of S-adenosylhomocysteine hydrolase deficiency

Pechhacker

Scipio

Vig

et al. 2020

Ophthalmic Genetics

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CRB1 Gene Mutation Causing Different Phenotypes of Leber Congenital Amaurosis in Siblings

Cited by 6 publications

References 13 publications

<p>Voretigene Neparvovec and Gene Therapy for Leber’s Congenital Amaurosis: Review of Evidence to Date</p>

<p>Voretigene Neparvovec and Gene Therapy for Leber’s Congenital Amaurosis: Review of Evidence to Date</p>

Identification of Arhgef12 and Prkci as genetic modifiers of retinal dysplasia in the Crb1rd8 mouse model

CRB1-related retinopathy overlapping the ocular phenotype of S-adenosylhomocysteine hydrolase deficiency

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