Abstract
Purpose :
Bietti’s crystalline dystrophy (BCD) is an inherited retinal disease caused by mutations in the CYP4V2 gene, which is implicated in the lipid metabolism. Cyp4v3 is the mouse ortholog of CYP4V2, and Cyp4v3-/- mice have been reported to show BCD-like retinal degeneration, although the phenotype varied among studies. We here established Cyp4v3-/- mice and analyzed the phenotype to evaluate the utility of this model in preclinical studies for BCD.
Methods :
Wild type (WT) and Cyp4v3-/- mice were bred with a normal diet or a high fat diet from postnatal week 4 (P4W). The observation with transmission electron microscope for the retinal structure and transcriptome analysis with bulk RNA-sequence (Gene Set Enrichment Analysis: GSEA) for the retinal pigment epithelium (RPE) and choroidal complex were conducted at P12W. The retinal thickness measurement in the HE section and assessment of photopic electroretinogram (ERG) were performed at P24W.
Results :
Cyp4v3-/- mice fed with a normal diet did not show any structural alteration compared with WT mice. On the other hand, Cyp4v3-/- mice fed with a high fat diet demonstrated the vacuole formation in the RPE at P12W, followed by thinning of retinal thickness (WT: 169.4 ± 25.7 μm, Cyp4v3-/-: 112.0 ± 32.4 μm; P=0.004) and the reduction of a-wave amplitude in cone ERG (WT: 13.6 ± 5.9 μV, Cyp4v3-/-: 12.2 ± 7.6 μV; P=0.047) at P24W. In RNA-seq analysis, the RPE choroid complex from high fat-loaded Cyp4v3-/- mice demonstrated the negative enrichment of the mitochondrial-involved pathways.
Conclusions :
RPE damage and Mitochondrial dysfunction may be the early pathology of BCD, and Cyp4v3-/- mice with a high diet load are an useful model for the research and development of BCD.
This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.