CYP4V2 – Bietti Crystalline Corneoretinal Dystrophy

CYP4V2 encodes a cytochrome P450 enzyme essential for ocular lipid metabolism. Bietti crystalline corneoretinal dystrophy (BCD) is an autosomal recessive disorder characterized by yellow crystalline deposits in the cornea and retina, progressive night blindness, constricted visual fields, and eventual chorioretinal atrophy.

Initial linkage and haplotype analyses refined the BCD locus on chromosome 4q35.1, identifying biallelic CYP4V2 mutations in 23 of 25 unrelated patients with BCD ([PMID:15042513]). Subsequent cohorts from diverse populations—including Japanese, Chinese, Iranian, Spanish, Lebanese, and Italian families—confirmed CYP4V2 as the causative gene in >200 unrelated probands, with segregation of disease status in consanguineous and multiplex pedigrees.

Inheritance is autosomal recessive, with over 80 pathogenic alleles reported including splice-site, nonsense, frameshift, and missense variants. A recurrent founder splice-site deletion‐insertion (c.802-8_810delinsGC) predominates in East Asian patients ([PMID:15042513]). Representative missense variant c.992A>C (p.His331Pro) illustrates loss-of-function due to protein instability.

CYP4V2 is highly expressed in retinal pigment epithelium and corneal epithelium, localizes to the endoplasmic reticulum, and hydroxylates ω-3 polyunsaturated fatty acids at rates comparable to hepatic CYP4F2. The p.His331Pro variant is undetectable by Western blot in transduced cells, indicating proteasomal degradation and loss of enzyme activity ([PMID:22772592]).

Proof-of-concept gene therapy using AAV2 vectors encoding codon-optimized CYP4V2 restored protein expression and enzymatic activity in HEK293, ARPE-19, patient iPSC-derived RPE cells, and human RPE/choroid explants, supporting feasibility of AAV-mediated supplementation ([PMID:35680963]).

Definitive genetic and functional evidence establish CYP4V2 mutations as the cause of BCD. Clinical genetic testing for CYP4V2 variants is recommended for patients presenting with crystalline retinal deposits and night blindness. Ongoing development of AAV-based gene therapy holds promise for restoring lipid metabolism and preserving vision.

Key Take-Home: Autosomal recessive CYP4V2 mutations cause Bietti crystalline corneoretinal dystrophy; genetic testing guides diagnosis and emerging AAV-mediated gene therapy offers a targeted treatment strategy.

References

• American Journal of Human Genetics | 2004 | Bietti crystalline corneoretinal dystrophy is caused by mutations in the novel gene CYP4V2. PMID:15042513
• Molecular Pharmacology | 2012 | CYP4V2 in Bietti's crystalline dystrophy: ocular localization, metabolism of ω-3-polyunsaturated fatty acids, and functional deficit of the p.H331P variant PMID:22772592
• Scientific Reports | 2022 | AAV2-mediated gene therapy for Bietti crystalline dystrophy provides functional CYP4V2 in multiple relevant cell models PMID:35680963

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