CRB2 mutation causes autosomal recessive retinitis pigmentosa

Chen, Xue; Jiang, Chao; Yang, Daidi; Sun, Ruxu; Wang, Min; Sun, Hong; Xu, Min; Zhou, Luyin; Chen, Mingkang; Xie, Ping; Yan, Biao; Zhao, Chunxia

doi:10.1016/j.exer.2018.12.018

Cited by 20 publications

(19 citation statements)

References 43 publications

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“…This is highly suggestive of the presence of a modifying factor. Variants of CRB2 have been associated with retinal aberrations and more recently a missense mutation of CRB2 has been found to cause retinitis pigmentosa [134,302]. Additionally, CRB2 is present in the fetal human retina in the first-trimester, whereas CRB1 expression starts from the second trimester [129].…”

Section: Crb1 and Leber Congenital Amaurosismentioning

confidence: 99%

Retinogenesis of the Human Fetal Retina: An Apical Polarity Perspective

Quinn

Wijnholds

2019

Genes

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The Crumbs complex has prominent roles in the control of apical cell polarity, in the coupling of cell density sensing to downstream cell signaling pathways, and in regulating junctional structures and cell adhesion. The Crumbs complex acts as a conductor orchestrating multiple downstream signaling pathways in epithelial and neuronal tissue development. These pathways lead to the regulation of cell size, cell fate, cell self-renewal, proliferation, differentiation, migration, mitosis, and apoptosis. In retinogenesis, these are all pivotal processes with important roles for the Crumbs complex to maintain proper spatiotemporal cell processes. Loss of Crumbs function in the retina results in loss of the stratified appearance resulting in retinal degeneration and loss of visual function. In this review, we begin by discussing the physiology of vision. We continue by outlining the processes of retinogenesis and how well this is recapitulated between the human fetal retina and human embryonic stem cell (ESC) or induced pluripotent stem cell (iPSC)-derived retinal organoids. Additionally, we discuss the functionality of in utero and preterm human fetal retina and the current level of functionality as detected in human stem cell-derived organoids. We discuss the roles of apical-basal cell polarity in retinogenesis with a focus on Leber congenital amaurosis which leads to blindness shortly after birth. Finally, we discuss Crumbs homolog (CRB)-based gene augmentation.

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Section: Crb1 and Leber Congenital Amaurosismentioning

confidence: 99%

Retinogenesis of the Human Fetal Retina: An Apical Polarity Perspective

Quinn

Wijnholds

2019

Genes

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“…In conclusion, our studies reveal a novel mechanism of action of CRB2, in which the action of a secreted variant, CRB2S, deriving from dmNes + RG, mediates local delamination, as part of a mechanism that establishes the central canal. The finding that CRB2S is expressed elsewhere in the CNS suggests it may operate more widely to promote local delamination: future studies are needed to establish whether its expression in SVL cells of the lateral ventricle, a recognized stem cell niche in the brain, promotes delamination associated with neuronal differentiation, and whether its expression in the eye is involved in dynamism of the retinal pigment epithelium (RPE), where Crb2 mutations trigger EMT and promote RPE degeneration (Alves et al, 2013;Alves et al, 2014;Chen et al, 2019) . More generally, our findings demonstrate how early patterning centres (dmNes+RG derive from roof plate cells) are maintained through life to support remodelling and maintenance, add to the evidence that, similar to Drosophila epithelial sheets, the vertebrate neuroepithelium is modelled by dynamic local cell-cell interactions, and reveals a cell non-autonomous action for CRB2S in neuroepithelial remodelling.…”

Section: Discussionmentioning

confidence: 99%

Crumbs2 mediates ventricular layer remodelling to form the adult spinal cord central canal

Tait

Chinnaiya

Murtaza

et al. 2019

Preprint

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In the spinal cord, the adult central canal forms through a poorly-understood process termed dorsal collapse that involves attrition and remodelling of the pseudostratified dorsal ventricular layer. Here we show, in mouse, that dorsal ventricular layer cells adjacent to midline Nestin (+) radial glia downregulate the apical polarity proteins Crumbs2 (CRB2) and aPKC and delaminate in a step-wise manner; concomitantly, Nestin (+) radial glial end-feet ratchet down, to repeat this process. Nestin (+) radial glia secrete a factor that promotes cell delamination. This activity is mimicked by a secreted variant of CRB2 (CRB2S), which is specifically expressed by dorsal midline Nestin (+) radial glia. In cultured cells, CRB2S associated with apical membranes and decreased cell cohesion. Analysis of Crb2 F/F /Nestin-Cre +/− mice further confirmed an essential role for CRB2 in dorsal collapse. We propose a model in which CRB2S promotes the progressive attrition of the ventricular layer without loss of overall integrity. This novel mechanism may operate more widely to promote orderly progenitor delamination.

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“…Until recently, no RP patients were described with mutations in the CRB2 gene. However, Chen et al (2019) discovered, using whole exome sequencing (WES), a homozygous CRB2 p.R1249G mutation in a consanguineous Chinese family presenting RP. This mutation disturbs the stability of CRB2 protein and thereby induces RPE degeneration, impairs RPE phagocytosis, and accelerates RPE apoptosis.…”

Section: Crb1 and Crb2 In Retinal Diseasesmentioning

confidence: 99%

“…Related to CRB, recent studies have shown that CRB2 but not CRB1 is expressed in the human RPE during the differentiation into retinal organoids (Quinn et al, 2019a). In addition, there are RP patients described with specific CRB2 variations expressed in RPE cells (Chen et al, 2019). Therefore, the method of generating hiPSC-RPE could be used to explore treatment possibilities for patients with specific variations in CRB2.…”

Section: Human-derived Retinal Modelsmentioning

confidence: 99%

Research Models and Gene Augmentation Therapy for CRB1 Retinal Dystrophies

2020

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Retinitis pigmentosa (RP) and Leber congenital amaurosis (LCA) are inherited degenerative retinal dystrophies with vision loss that ultimately lead to blindness. Several genes have been shown to be involved in early onset retinal dystrophies, including CRB1 and RPE65. Gene therapy recently became available for young RP patients with variations in the RPE65 gene. Current research programs test adeno-associated viral gene augmentation or editing therapy vectors on various disease models mimicking the disease in patients. These include several animal and emerging human-derived models, such as human-induced pluripotent stem cell (hiPSC)-derived retinal organoids or hiPSC-derived retinal pigment epithelium (RPE), and human donor retinal explants. Variations in the CRB1 gene are a major cause for early onset autosomal recessive RP with patients suffering from visual impairment before their adolescence and for LCA with newborns experiencing severe visual impairment within the first months of life. These patients cannot benefit yet from an available gene therapy treatment. In this review, we will discuss the recent advances, advantages and disadvantages of different CRB1 human and animal retinal degeneration models. In addition, we will describe novel therapeutic tools that have been developed, which could potentially be used for retinal gene augmentation therapy for RP patients with variations in the CRB1 gene.

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CRB2 mutation causes autosomal recessive retinitis pigmentosa

Cited by 20 publications

References 43 publications

Retinogenesis of the Human Fetal Retina: An Apical Polarity Perspective

Retinogenesis of the Human Fetal Retina: An Apical Polarity Perspective

Crumbs2 mediates ventricular layer remodelling to form the adult spinal cord central canal

Research Models and Gene Augmentation Therapy for CRB1 Retinal Dystrophies

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