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A novel and efficient murine model of Bietti crystalline dystrophy.

ABSTRACT: Bietti crystalline dystrophy (BCD) is an autosomal recessive inherited retinal disease, resulting in blindness in most patients. The etiology and development mechanism of it remain unclear. Given the defects in previous mouse models of BCD, we generated a new Cyp4v3-/- mouse model, using CRISPR/Cas9 technology, for investigating the pathogenesis of BCD. We estimated the ocular phenotypes by fundus imaging, optical coherence tomography (OCT) and full-field scotopic electroretinography, and investigated the histological features by Hematoxylin and Eosin staining, Oil Red O staining and immunofluorescence. This model effectively exhibited age-related progression that mimicked the human ocular phenotypes. Moreover, gas chromatography-mass spectrometry and RNA-seq analysis indicated that the defect of Cyp4v3 led to the abnormal lipid metabolism, inflammation activation and oxidative stress of retina. Notably, inflammation activation and oxidative stress could also promote the progression of BCD in light-induced retinal degeneration. In conclusion, our data provided evidence that we established a novel and more effective Cyp4v3 knockout preclinical mouse model for BCD, which served as a useful tool for evaluating the effect of drugs and gene therapy in vivo.

SUBMITTER: Wang Y

PROVIDER: S-EPMC8906172 | biostudies-literature | 2022 Mar

REPOSITORIES: biostudies-literature

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A novel and efficient murine model of Bietti crystalline dystrophy.

Wang Yafang Y Liu Yang Y Liu Shu S Li Xiaomeng X Liu Xinxin X Jiao Ming M Yang Yuqin Y Luo Xueting X Wang Fenghua F Wan Xiaoling X Sun Xiaodong X

Disease models & mechanisms 20220301 3

Bietti crystalline dystrophy (BCD) is an autosomal recessive inherited retinal disease, resulting in blindness in most patients. The etiology and development mechanism of it remain unclear. Given the defects in previous mouse models of BCD, we generated a new Cyp4v3-/- mouse model, using CRISPR/Cas9 technology, for investigating the pathogenesis of BCD. We estimated the ocular phenotypes by fundus imaging, optical coherence tomography (OCT) and full-field scotopic electroretinography, and invest ...[more]

PMID: 35230417

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Project description:PurposeBietti crystalline dystrophy (BCD) is a progressive retinal degenerative disease primarily characterized by numerous crystal-like deposits and degeneration of retinal pigment epithelium (RPE) and photoreceptor cells. CYP4V2 (cytochrome P450 family 4 subfamily V member 2) is currently the only disease-causing gene for BCD. We aimed to generate a zebrafish model to explore the functional role of CYP4V2 in the development of BCD and identify potential therapeutic targets for future studies.MethodsThe cyp4v7 and cyp4v8 (homologous genes of CYP4V2) knockout zebrafish lines were generated by CRISPR/Cas9 technology. The morphology of photoreceptor and RPE cells and the accumulation of lipid droplets in RPE cells were investigated at a series of different developmental stages through histological analysis, immunofluorescence, and lipid staining. Transcriptome analysis was performed to investigate the changes in gene expression of RPE cells during the progression of BCD.ResultsProgressive retinal degeneration including RPE atrophy and photoreceptor loss was observed in the mutant zebrafish as early as seven months after fertilization. We also observed the excessive accumulation of lipid droplets in RPE cells from three months after fertilization, which preceded the retinal degeneration by several months. Transcriptome analysis suggested that multiple metabolism pathways, especially the lipid metabolism pathways, were significantly changed in RPE cells. The down-regulation of the peroxisome proliferator-activated receptor α (PPARα) pathway was further confirmed in the mutant zebrafish and CYP4V2-knockdown human RPE-1 cells.ConclusionsOur work established an animal model that recapitulates the symptoms of BCD patients and revealed that abnormal lipid metabolism in RPE cells, probably caused by dysregulation of the PPARα pathway, might be the main and direct consequence of CYP4V2 deficiency. These findings will deepen our understanding of the pathogenesis of BCD and provide potential therapeutic approaches.

Project description:BackgroundBietti crystalline dystrophy (BCD) is a distinct entity of retinitis pigmentosa with a wide range of genotypic and phenotypic variabilities. The goal of the present study was to investigate the morphological, functional and genetic features of BCD.MethodsA full series of multimodal imaging was performed in four Chinese patients with BCD, including fundus photography, fundus autofluorescence, fundus fluorescein angiography (FFA), indocyanine green (ICG) angiography, optical coherence tomography (OCT) and microperimetry. Electrophysiological tests including full-field electroretinography (ERG) and multifocal ERG were employed. CYP4V2 gene sequencing was performed.ResultsIntraretinal crystalline deposits were observed in fundus photographs in all patients. The crystals were better appreciated in infrared images. Autofluorescence imaging demonstrated multifocal patchy hypofluorescence, suggesting massive RPE atrophy. FFA and ICG angiography further confirmed atrophy of the RPE and the underlying choroidal vessels. OCT revealed disruption of the photoreceptors, RPE and the choroid. Outer retinal tubulations (ORTs) confining to the outer nuclear layer were detected in three out of four patients. Full-field ERG showed markedly diminished responses. Multifocal ERG displayed reduced central and peripheral responses in a patient with normal vision. Gene sequencing identified two deletion mutations in CYP4V2, c.802_807del and c.810delT. BCD complicated by choroidal neovascularization (CNV) was diagnosed in one patient, and intravitreal anti-vascular endothelial growth factor (VEGF) injection was given with favorable response.ConclusionsMultimodal imaging features and electrophysiological findings of BCD patients were comprehensively discussed. A novel deletion mutation, c.802_807del, in the CYP4V2 gene was reported. ORTs are important changes in the outer retina of BCD patients, further investigation of this structure may provide insights into pathology of BCD. Intravitreal anti-VEGF therapy was effective for treatment of BCD complicated by CNV.

Dataset Information

A novel and efficient murine model of Bietti crystalline dystrophy.

Publications

A novel and efficient murine model of Bietti crystalline dystrophy.

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