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Yuwei Wang, Xiaomeng Li, Yang Yu, Jian Liang, Yang Liu, Yuhong Chen, Xinyue Bai, Jieqiong Chen, Fenghua Wang, Xueting Luo, Xiaodong Sun; Modeling Cone/Cone–Rod Dystrophy Pathology by AAV-Mediated Overexpression of Mutant CRX Protein in the Mouse Retina. Trans. Vis. Sci. Tech. 2021;10(7):25. doi: https://doi.org/10.1167/tvst.10.7.25.
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This study aims to evaluate the pathogenesis of cone/cone–rod dystrophy (CoD/CoRD) caused by a cone–rod homeobox (CRX) mutation, which was identified in a Chinese family, through adeno-associated virus (AAV)-mediated overexpression of mutant CRX protein in the mouse retina.
Comprehensive ophthalmologic examinations were performed for the pedigree members of a Chinese family with CoD/CoRD. Whole exome sequencing and Sanger sequencing were performed to determine the genetic cause of the disease. Furthermore, AAV vectors were used to construct AAV-CRX-mut-HA, which was transfected into mouse photoreceptor cells to clarify the pathogenesis of the mutant CRX.
Fundus photography and optical coherence tomography images displayed features that were consistent with CoD/CoRD, including macular atrophy and photoreceptor layer thinning. Electroretinogram analysis indicated an obvious decrease in photopic responses or both scotopic and photopic responses in affected individuals. A frameshift variant c.611delC (p.S204fs) in CRX was cosegregated with the disease in this family. AAV-CRX-mut-HA that subretinally injected into the C57BL/6 mice generally transfected the outer nuclear layer, leading to the loss of cone and rod photoreceptor cells, abnormal expression of CRX target genes, and a decrease in electroretinogram responses.
AAV-mediated overexpression of CRX[S204fs] in the mouse retina led to a CoRD-like phenotype and showed the possible pathogenesis of the antimorphic CRX mutation.
This study provides a modeling method to evaluate the pathogenesis of CoD/CoRD and other inherited retinal dystrophies caused by distinct gain-of-function mutations.
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