Loss of CRB2 in Müller glial cells modifies a CRB1-associated retinitis pigmentosa phenotype into a Leber congenital amaurosis phenotype
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- Peter M Quinn
- Department of Ophthalmology, Leiden University Medical Center, RC Leiden, The Netherlands
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- Aat A Mulder
- Department of Cell & Chemical Biology, Leiden University Medical Center (LUMC), RC Leiden, The Netherlands
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- C Henrique Alves
- Department of Ophthalmology, Leiden University Medical Center, RC Leiden, The Netherlands
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- Mélissa Desrosiers
- Department of Therapeutics, Institut de la Vision, Sorbonne Universités, UPMC Univ Paris, UMR_S INSERM, CNRS, UMR, Paris, France
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- Sharon I de Vries
- Department of Axonal Signaling, Netherlands Institute for Neuroscience, Royal Netherlands Academy of Arts and Sciences (KNAW), BA Amsterdam, The Netherlands
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- Jan Klooster
- Department of Retina Signal Processing, Netherlands Institute for Neuroscience, Royal Netherlands Academy of Arts and Sciences (KNAW), BA Amsterdam, The Netherlands
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- Deniz Dalkara
- Department of Therapeutics, Institut de la Vision, Sorbonne Universités, UPMC Univ Paris, UMR_S INSERM, CNRS, UMR, Paris, France
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- Abraham J Koster
- Department of Cell & Chemical Biology, Leiden University Medical Center (LUMC), RC Leiden, The Netherlands
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- Carolina R Jost
- Department of Cell & Chemical Biology, Leiden University Medical Center (LUMC), RC Leiden, The Netherlands
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- Jan Wijnholds
- Department of Ophthalmology, Leiden University Medical Center, RC Leiden, The Netherlands
抄録
<jats:title>Abstract</jats:title> <jats:p>Variations in the human Crumbs homolog-1 (CRB1) gene lead to an array of retinal dystrophies including early onset of retinitis pigmentosa (RP) and Leber congenital amaurosis (LCA) in children. To investigate the physiological roles of CRB1 and CRB2 in retinal Müller glial cells (MGCs), we analysed mouse retinas lacking both proteins in MGC. The peripheral retina showed a faster progression of dystrophy than the central retina. The central retina showed retinal folds, disruptions at the outer limiting membrane, protrusion of photoreceptor nuclei into the inner and outer segment layers and ingression of photoreceptor nuclei into the photoreceptor synaptic layer. The peripheral retina showed a complete loss of the photoreceptor synapse layer, intermingling of photoreceptor nuclei within the inner nuclear layer and ectopic photoreceptor cells in the ganglion cell layer. Electroretinography showed severe attenuation of the scotopic a-wave at 1 month of age with responses below detection levels at 3 months of age. The double knockout mouse retinas mimicked a phenotype equivalent to a clinical LCA phenotype due to loss of CRB1. Localization of CRB1 and CRB2 in non-human primate (NHP) retinas was analyzed at the ultrastructural level. We found that NHP CRB1 and CRB2 proteins localized to the subapical region adjacent to adherens junctions at the outer limiting membrane in MGC and photoreceptors. Our data suggest that loss of CRB2 in MGC aggravates the CRB1-associated RP-like phenotype towards an LCA-like phenotype.</jats:p>
収録刊行物
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- Human Molecular Genetics
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Human Molecular Genetics 28 (1), 105-123, 2018-09-19
Oxford University Press (OUP)