Human<i>CRB1</i>-Associated Retinal Degeneration: Comparison with the<i>rd8 Crb1</i>-Mutant Mouse Model

Alemán, Tomás S.; Cideciyan, Artur V.; Aguirre, Geoffrey K.; Huang, Wei; Mullins, Cristina L.; Román, Alejandro J.; Sumaroka, Alexander; Olivares, Melani B.; Tsai, Frank F.; Schwartz, Sharon; Vandenberghe, Luk; Limberis, Maria P.; Stone, Edwin M.; Bell, Peter; Wilson, James M.; Jacobson, Samuel G.

doi:10.1167/iovs.11-7701

Cited by 99 publications

(116 citation statements)

References 53 publications

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“…Small hyperreflective dots without shadowing, previously described by Aleman et al, 12 were found in the inner and outer retinal layers at different depths from the vitreoretinal surface in 11 of 11 patients (100%; Fig 4AeD). The origin of these hyperreflectivities was unclear.…”

Section: Findings On Retinal Imagingsupporting

confidence: 67%

“…Previous reports have found Coats-like exudates in 0% to 25%. 12,17,18,29 Full-field electroretinography responses became unrecordable on average in the second decade of life in 50% of our RP cohort and in the first decade of life in our LCA cohort, with high intrafamilial and interfamilial variability in the RP group. These electroretinography results indicate that most patients with CRB1-associated RP and LCA are affected by early panretinal rod and cone dysfunction.…”

Section: Discussionmentioning

confidence: 69%

“…The retinal laminar structure on SD OCT in our patient cohort was relatively intact compared with that of earlier studies that described coarse lamination, defined as unclearly delineated retinal layers, in mice and patients with CRB1-associated retinal dystrophies, in both thickened and atrophic areas of retina. 3,12,13,34 Although our findings suggest progressive over congenital changes, a limitation of this study is the lack of longitudinal OCT follow-up, which could clarify if such coarse OCT lamination is the result of a congenital or a degenerative process. The finding of peripheral loss of delineation with central islands of intact lamination in an RP phenotype with centripetal progression would support the notion of intact retinal lamination at birth followed by progressive retinal dystrophy with consequent loss of outer retinal lamination in the affected areas.…”

Section: Discussionmentioning

confidence: 71%

“…Previous studies have reported retinal thinning with advancing age. 12,17 A relatively disorganized retina with suboptimally visible retinal layers on OCT was present in 9% of patients, and outer retinal layers were more difficult to discern than inner retinal layers in 36% of the total population. The retinal laminar structure on SD OCT in our patient cohort was relatively intact compared with that of earlier studies that described coarse lamination, defined as unclearly delineated retinal layers, in mice and patients with CRB1-associated retinal dystrophies, in both thickened and atrophic areas of retina.…”

Section: Discussionmentioning

confidence: 99%

“…10,11 CRB1-associated dystrophies, unlike other inherited retinal dystrophies, commonly are associated with retinal thickening on OCT. 12 However, normal or reduced retinal thickness also has been described. 13,14 Specific features associated with CRB1 gene mutations like Coats-like exudates, nanophthalmos, keratoconus, and macular dystrophy are not present consistently.…”

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confidence: 99%

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Genotypic and Phenotypic Characteristics of CRB1 -Associated Retinal Dystrophies

et al. 2017

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Purpose: To describe the phenotype, long-term clinical course, clinical variability, and genotype of patients with CRB1-associated retinal dystrophies.Design: Retrospective cohort study. Participants: Fifty-five patients with CRB1-associated retinal dystrophies from 16 families. Methods: A medical record review of 55 patients for age at onset, medical history, initial symptoms, bestcorrected visual acuity, ophthalmoscopy, fundus photography, full-field electroretinography (ffERG), Goldmann visual fields (VFs), and spectral-domain optical coherence tomography.Main Outcome Measures: Age at onset, visual acuity survival time, visual acuity decline rate, and electroretinography and imaging findings.Results: A retinitis pigmentosa (RP) phenotype was present in 50 patients, 34 of whom were from a Dutch genetic isolate (GI), and 5 patients had a Leber congenital amaurosis phenotype. The mean follow-up time was 15.4 years (range, 0e55.5 years). For the RP patients, the median age at symptom onset was 4.0 years. In the RP group, median ages for reaching low vision, severe visual impairment, and blindness were 18, 32, and 44 years, respectively, with a visual acuity decline rate of 0.03 logarithm of the minimum angle of resolution per year. The presence of a truncating mutation did not alter the annual decline rate significantly (P ¼ 0.75). Asymmetry in visual acuity was found in 31% of patients. The annual VF decline rate was 5% in patients from the genetic isolate, which was significantly faster than in non-GI patients (P < 0.05). Full-field electroretinography responses were extinguished in 50% of patients, were pathologically attenuated without a documented rod or cone predominance in 30% of patients, and showed a rodecone dysfunction pattern in 20% of RP patients. Cystoid fluid collections in the macula were found in 50% of RP patients.Conclusions: Mutations in the CRB1 gene are associated with a spectrum of progressive retinal degeneration. Visual acuity survival analyses indicate that the optimal intervention window for subretinal gene therapy is within the first 2 to 3 decades of life. Ophthalmology 2017;124:884-895 ª 2017 by the American Academy of Ophthalmology Supplemental material available at www.aaojournal.org.Mutations in the CRB1 gene are associated with a wide variety of severe retinal dystrophies with variable phenotypes, including panretinal dystrophies such as retinitis pigmentosa (RP), Leber congenital amaurosis (LCA), and coneerod dystrophy, as well as central phenotypes such as isolated macular dystrophy and foveal retinoschisis. Retinitis pigmentosa is a clinically and genetically heterogeneous disorder. Mutations in the CRB1 gene have been associated with RP12, a distinct form of RP characterized by preservation of para-arteriolar retinal pigment epithelium, progressive visual field (VF) loss starting from the first decade of life, and early macular involvement. 4 Other common features are hyperopia and optic disc drusen, previously described in a Dutch genetic isolate (GI). 5Classic forms of earl...

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Section: Findings On Retinal Imagingsupporting

confidence: 67%

Section: Discussionmentioning

confidence: 69%

Section: Discussionmentioning

confidence: 71%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Genotypic and Phenotypic Characteristics of CRB1 -Associated Retinal Dystrophies

et al. 2017

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Current perspectives in Leber congenital amaurosis type 8 mouse modeling

Nahar

Cho

2022

Developmental Dynamics

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Mutations in the CRB1 (Crumbs homolog 1) cause rare retinal diseases like retinitis pigmentosa type 12 (RP12) and Leber congenital amaurosis type 8 (LCA8). RP12 results in progressively worsening peripheral vision, whereas LCA8 causes severe visual impairment at birth or in early life. While several mouse models have been proposed for RP12, few replicate the full spectrum of human LCA8 pathology, such as disorganized retinal layering, abnormal retinal thickening, pigmentary defects, hyperreflective lesions, and severely attenuated electroretinogram responses at birth. Six models have been proposed utilizing the Cre-loxP system to delete candidate genes in specific retinal cell types and developmental stages. The model ablating Crb1 and its homolog Crb2 (using mRx-Cre) from the beginning of the eye development is the most complete as it shows blindness during the eye-opening stage, pigmentary defects in the RPE, ganglion cell layer heterotopia, disruption of retinal lamination, and acellular patches. LCA8 represents a unique type of retinal dystrophy among LCA subtypes, driven by dysfunctional retinal progenitor cells during eye development. In contrast, other LCA types and RP12 are caused by photoreceptor defects. Therefore, the most accurate LCA8-like mouse model must target both alleles of the Crb1 and Crb2 genes in the optic vesicle or earlier.

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Clarin‐1 expression in adult mouse and human retina highlights a role of Müller glia in Usher syndrome

Bolch

Santiago

et al. 2019

The Journal of Pathology

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Usher syndrome type 3 (USH3) is an autosomal recessively inherited disorder caused by mutations in the gene clarin-1 (CLRN1), leading to combined progressive hearing loss and retinal degeneration. The cellular distribution of CLRN1 in the retina remains uncertain, either because its expression levels are low or because its epitopes are masked. Indeed, in the adult mouse retina, Clrn1 mRNA is developmentally downregulated, detectable only by RT-PCR. In this study we used the highly sensitive RNAscope in situ hybridization assay and single-cell RNA-sequencing techniques to investigate the distribution of Clrn1 and CLRN1 in mouse and human retina, respectively. We found that Clrn1 transcripts in mouse tissue are localized to the inner retina during postnatal development and in adult stages. The pattern of Clrn1 mRNA cellular expression is similar in both mouse and human adult retina, with CLRN1 transcripts being localized in Müller glia, and not photoreceptors. We generated a novel knock-in mouse with a hemagglutinin (HA) epitope-tagged CLRN1 and showed that CLRN1 is expressed continuously at the protein level in the retina. Following enzymatic deglycosylation and immunoblotting analysis, we detected a single CLRN1-specific protein band in homogenates of mouse and human retina, consistent in size with the main CLRN1 isoform. Taken together, our results implicate Müller glia in USH3 pathology, placing this cell type to the center of future mechanistic and therapeutic studies to prevent vision loss in this disease.

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HumanCRB1-Associated Retinal Degeneration: Comparison with therd8 Crb1-Mutant Mouse Model

Cited by 99 publications

References 53 publications

Genotypic and Phenotypic Characteristics of CRB1 -Associated Retinal Dystrophies

Genotypic and Phenotypic Characteristics of CRB1 -Associated Retinal Dystrophies

Current perspectives in Leber congenital amaurosis type 8 mouse modeling

Clarin‐1 expression in adult mouse and human retina highlights a role of Müller glia in Usher syndrome

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