CRB2 acts as a modifying factor of CRB1-related retinal dystrophies in mice

Pellissier, Lucie P.; Lundvig, Ditte M. S.; Tanimoto, Naoyuki; Klooster, Jan; Vos, Rogier M.; Richard, Fabrice; Sothilingam, Vithiyanjali; Garrido, Marina Garcia; Bivic, André Le; Seeliger, Mathias W.; Wijnholds, Jan

doi:10.1093/hmg/ddu089

Cited by 47 publications

(86 citation statements)

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“…The high interindividual variability in disease onset, retinal thickness on OCT, and VF sizes supports the earlier suggestion of the involvement of genetic and possibly environmental modifiers in CRB1-associated disease. 47 In mice, Crb2 is a modifier of Crb1, 48 and human CRB2 can rescue the phenotype in mice lacking Crb1. 15 Sequence variants in human CRB2 cause a renal and cerebral syndrome with possible loss of BCVA and EZ loss on OCT in some patients.…”

Section: Discussionmentioning

confidence: 99%

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: Discussionmentioning

confidence: 99%

Genotypic and Phenotypic Characteristics of CRB1 -Associated Retinal Dystrophies

et al. 2017

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“…Knockout Crb1 -/-, knockin Crb1 C249W/-, and naturally occurring Crb1 rd8/rd8 mice show mild retinal disorganization that is particularly marked in the inferior retinal quadrant [van de Pavert et al, 2007;Pellissier et al, 2014]. Mouse models of Crb1 loss of function together with models of Crb2 and Pals1 loss of function also display some of the phenotypic features associated with human CRB1 variants, including focal laminar disorgani zation, pseudorosette formation, photoreceptor degeneration, and functional impairment in the electroretinogram [Alves et al, 2013[Alves et al, , 2014Kim et al, 2015].…”

Section: Molecular Geneticsmentioning

confidence: 99%

The Family of Crumbs Genes and Human Disease

Slavotinek¹

2016

Mol Syndromol

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The family of vertebrate Crumbs proteins, homologous to Drosophila Crumbs (Crb), share large extracellular domains with epidermal growth factor-like repeats and laminin-globular domains, a single transmembrane domain, and a short intracellular C-terminus containing a single membrane proximal 4.1/ezrin/radixin/moesin-binding domain and PSD-95/Discs large/ZO-1-binding motifs. There are 3 Crb genes in humans - Crumbs homolog-1 (CRB1), Crumbs homolog-2 (CRB2), and Crumbs homolog-3 (CRB3). Bilallelic loss-of-function mutations in CRB1 cause visual impairment, with Leber's congenital amaurosis and retinitis pigmentosa, whereas CRB2 mutations are associated with raised maternal serum and amniotic fluid alpha feto-protein levels, ventriculomegaly/hydrocephalus, and renal disease, ranging from focal segmental glomerulosclerosis to congenital Finnish nephrosis. CRB3 has not yet been associated with human disease. In this review, we summarize the phenotypic findings associated with deleterious sequence variants in CRB1 and CRB2. We discuss the mutational spectrum, animal models of loss of function for both genes and speculate on the likely mechanisms of disease.

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“…This apical localization is essential for maintaining the polarity of the epithelia and adhesion among retinal and lens cells. Therefore, retinas with deficient Pals1 or Crb1, Crb2 and Crb1/Crb2 display laminar disorganization, retinal folding and pseudorosette formation (Alves et al, 2014a; Alves et al, 2013; Cho et al, 2012; Park et al, 2011; Pellissier et al, 2014; Zou et al, 2013). The specificity of the antibodies used in the present study was previously demonstrated.…”

Section: Resultsmentioning

confidence: 99%

Common and distinctive localization patterns of Crumbs polarity complex proteins in the mammalian eye

Kim

Song

Karnam

et al. 2015

Gene Expression Patterns

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Crumbs polarity complex proteins are essential for cellular and tissue polarity, and for adhesion of epithelial cells. In epithelial tissues deletion of any of three core proteins disrupts localization of the other proteins, indicating structural and functional interdependence among core components. Despite previous studies of function and co-localization that illustrated the properties that these proteins share, it is not known whether an individual component of the complex plays a distinct role in a unique cellular and developmental context. In order to investigate this question, we primarily used confocal imaging to determine the expression and subcellular localization of the core Crumbs polarity complex proteins during ocular development. Here we show that in developing ocular tissues core Crumbs polarity complex proteins, Crb, Pals1 and Patj, generally appear in an overlapping pattern with some exceptions. All three core complex proteins localize to the apical junction of the retinal and lens epithelia. Pals1 is also localized in the Golgi of the retinal cells and Patj localizes to the nuclei of the apically located subset of progenitor cells. These findings suggest that core Crumbs polarity complex proteins exert common and independent functions depending on cellular context.

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CRB2 acts as a modifying factor of CRB1-related retinal dystrophies in mice

Cited by 47 publications

References 43 publications

Genotypic and Phenotypic Characteristics of CRB1 -Associated Retinal Dystrophies

Genotypic and Phenotypic Characteristics of CRB1 -Associated Retinal Dystrophies

The Family of Crumbs Genes and Human Disease

Common and distinctive localization patterns of Crumbs polarity complex proteins in the mammalian eye

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