Cyp4v3 is the murine ortholog of human CYP4V2 [1,2,3,4,5,6,7,8,9]. While the exact function of Cyp4v3 remains under study, it is associated with lipid metabolic pathways, given that mutations in its human ortholog CYP4V2 cause Bietti crystalline corneoretinal dystrophy (BCD), a disease characterized by lipid metabolic disruption [3]. Understanding Cyp4v3 is crucial as it can provide insights into BCD pathogenesis and potential treatments. Genetic models, especially gene knockout mouse models, are valuable tools for studying Cyp4v3.

Cyp4v3 knockout (KO) mice recapitulate several features of BCD, such as retinal crystalline deposits, atrophy and degeneration of retinal pigment epithelium (RPE) cells, and ERG amplitude decline, indicating age-related disease progression similar to human BCD patients [1]. Lipid profiling and transcriptome analysis of RPE cells from Cyp4v3 KO mice showed increased polyunsaturated fatty acids (PUFAs), changes in genes involved in iron homeostasis (notably upregulation of NCOA4), and ferroptosis-related characteristics like mitochondrial defects, lipid peroxidation, and ROS accumulation [2]. A high-fat diet exacerbated the BCD-like phenotype in Cyp4v3 KO mice, accelerating retinal lesions [9]. Gene-replacement therapy using AAV2/8-CAG-CYP4V2 in Cyp4v3 KO mice restored vision, as shown by elevated electroretinogram amplitude and ameliorated RPE degeneration [3].

In conclusion, model-based research reveals that Cyp4v3 is closely related to lipid metabolism and iron homeostasis in the context of BCD. The Cyp4v3 KO mouse models have been instrumental in understanding the pathogenesis of BCD, such as the role of ferroptosis, and evaluating potential therapeutic strategies like gene-replacement therapy for this currently untreatable disease [1,2,3,9].

References:

1. Jia, R X, Jiang, S W, Zhao, L, Yang, L P. . [Generation and characterization of Cyp4v3 gene knockout mice]. In Beijing da xue xue bao. Yi xue ban = Journal of Peking University. Health sciences, 53, 1099-1106. doi:. https://pubmed.ncbi.nlm.nih.gov/34916689/

2. Shen, Chang, Yang, Qianjie, Chen, Kuangqi, Shen, Ye, Cui, Hongguang. 2024. Uncovering the role of ferroptosis in Bietti crystalline dystrophy and potential therapeutic strategies. In Cell communication and signaling : CCS, 22, 359. doi:10.1186/s12964-024-01710-x. https://pubmed.ncbi.nlm.nih.gov/38992691/

3. Jia, Ruixuan, Meng, Xiang, Chen, Shaohong, Liu, Xiaozhen, Yang, Liping. . AAV-mediated gene-replacement therapy restores viability of BCD patient iPSC derived RPE cells and vision of Cyp4v3 knockout mice. In Human molecular genetics, 32, 122-138. doi:10.1093/hmg/ddac181. https://pubmed.ncbi.nlm.nih.gov/35925866/

4. Yang, Richard Rui. 2023. A patient advocating for transparent science in rare disease research. In Orphanet journal of rare diseases, 18, 14. doi:10.1186/s13023-022-02557-6. https://pubmed.ncbi.nlm.nih.gov/36658594/

5. Safdar, Huma, Cleuren, Audrey C A, Cheung, Ka Lei, Reitsma, Pieter H, van Vlijmen, Bart J M. 2013. Regulation of the F11, Klkb1, Cyp4v3 gene cluster in livers of metabolically challenged mice. In PloS one, 8, e74637. doi:10.1371/journal.pone.0074637. https://pubmed.ncbi.nlm.nih.gov/24066149/

6. Wang, Yafang, Liu, Yang, Liu, Shu, Wan, Xiaoling, Sun, Xiaodong. 2022. A novel and efficient murine model of Bietti crystalline dystrophy. In Disease models & mechanisms, 15, . doi:10.1242/dmm.049222. https://pubmed.ncbi.nlm.nih.gov/35230417/

7. Lockhart, Catherine M, Nakano, Mariko, Rettie, Allan E, Kelly, Edward J. 2014. Generation and characterization of a murine model of Bietti crystalline dystrophy. In Investigative ophthalmology & visual science, 55, 5572-81. doi:10.1167/iovs.13-13717. https://pubmed.ncbi.nlm.nih.gov/25118264/

8. Stark, Katarina, Guengerich, F Peter. . Characterization of orphan human cytochromes P450. In Drug metabolism reviews, 39, 627-37. doi:. https://pubmed.ncbi.nlm.nih.gov/17786643/

9. Qu, Bin, Wu, Shijing, Jiao, Guanyi, Sui, Ruifang, Li, Wei. 2020. Treating Bietti crystalline dystrophy in a high-fat diet-exacerbated murine model using gene therapy. In Gene therapy, 27, 370-382. doi:10.1038/s41434-020-0159-3. https://pubmed.ncbi.nlm.nih.gov/32483213/