CRB2 mutation causes autosomal recessive retinitis pigmentosa
Autor: | Qinghuai Liu, Luyin Zhou, Xue Chen, Min Wang, Biao Yan, Ruxu Sun, Mingkang Chen, Hong Sun, Chen Zhao, Chao Jiang, Min Xu, Ping Xie, Daidi Yang |
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Rok vydání: | 2018 |
Předmět: |
0301 basic medicine
China Epithelial-Mesenchymal Transition Mutation Missense Visual Acuity Retinal Pigment Epithelium Biology medicine.disease_cause 03 medical and health sciences Cellular and Molecular Neuroscience Consanguinity 0302 clinical medicine Asian People Retinitis pigmentosa Exome Sequencing medicine Missense mutation Humans RNA Messenger Mutation CRB1 Retinal pigment epithelium Genetic heterogeneity Wild type Membrane Proteins Middle Aged medicine.disease Molecular biology Phenotype Sensory Systems Pedigree Ophthalmology 030104 developmental biology medicine.anatomical_structure 030221 ophthalmology & optometry Female Carrier Proteins Retinitis Pigmentosa |
Zdroj: | Experimental eye research. 180 |
ISSN: | 1096-0007 |
Popis: | Retinitis pigmentosa (RP), the most common form of inherited retinal dystrophies, exhibits significant genetic heterogeneity. The crumbs homolog 2 (CRB2) protein, together with CRB1 and CRB3, belongs to the Crumbs family. Given that CRB1 mutations account for 4% of RP cases, the role of CRB2 mutations in RP etiology has long been hypothesized but never confirmed. Herein, we report the identification of CRB2 as a novel RP causative gene in a Chinese consanguineous family and have analyzed its pathogenic effects. Comprehensive ophthalmic and systemic evaluations confirmed the clinical diagnosis of the two patients in this family as RP. WES revealed a homozygous missense mutation, CRB2 p.R1249G, to segregate the RP phenotype, which was highly conserved among multiple species. In vitro cellular study revealed that this mutation not only interrupted the stability of the transcribed CRB2 mRNA and the encoded CRB2 protein, but also interfered with the wild type CRB2 mRNA/protein and decreased their expression. This mutation was also shown to trigger epithelial-mesenchymal transition (EMT) in retinal pigment epithelium (RPE) cells, thus impairing regular RPE phagocytosis and induce RPE degeneration and apoptosis. Thus, we conclude that CRB2 p.R1249G mutation causes RP via accelerating EMT, dysfunction and loss of RPE cells, and establish CRB2 as a novel Crumbs family member associated with non-syndromic RP. We provide important hints for understanding of CRB2 defects and retinopathy, and for the involvement of EMT of RPE cells in RP pathogenesis. |
Databáze: | OpenAIRE |
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