HGNC Approved Gene Symbol: CYP4V2
SNOMEDCT: 312927001;
Cytogenetic location: 4q35.1-q35.2 Genomic coordinates (GRCh38) : 4:186,191,567-186,213,463 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 4q35.1-q35.2 | Bietti crystalline corneoretinal dystrophy | 210370 | Autosomal recessive | 3 |
By 3-prime and 5-prime RACE and PCR of a human retina cDNA library, Li et al. (2004) obtained a 2,041-bp CYP4V2 cDNA, which encodes a deduced 525-amino acid protein with homology to members of CYP450 family 4. PCR of human tissue-specific cDNA showed expression of CYP4V2 in heart, brain, placenta, lung, liver, skeletal muscle, kidney, pancreas, retina, retinal pigment epithelium, and lymphocytes. Highest expression was found in retina. The expression of CYP4V2 in a wide variety of tissues is consistent with inclusions and their clinical sequelae found in the cornea, retina, and lymphocytes.
The CYP4V2 gene contains 11 exons spanning 19 kb. The coding sequence begins in exon 1 and continues through exon 11 (Li et al., 2004).
In a study of 10 families with Bietti crystalline corneoretinal dystrophy (BCD; 210370), Jiao et al. (2000) showed linkage of the disorder to 4q35-qter (maximum lod = 5.31 with D4S2299 at theta = 0.0). Using haplotype and linkage analyses, Li et al. (2004) refined the BCD critical region to a region of 4q35.1 flanked centromerically by D4S2924.
The predicted transmembrane segment of CYP4V2 resides near the N terminus, followed by a globular structural domain typical of the CYP450 family. The globular domain of CYP4V2 comprises 18 helices and beta structural segments. The heme group is located close to the surface of the protein, coordinated by the I helix toward the protein interior and the L helix superficially (Li et al., 2004).
Bietti crystalline corneoretinal dystrophy (BCD; 210370) is an autosomal recessive retinal dystrophy characterized by multiple glistening intraretinal crystals scattered over the fundus, a characteristic degeneration of the retina, and sclerosis of the choroidal vessels, ultimately resulting in progressive night blindness and constriction of the visual field. In 23 of 25 unrelated patients with BCD, Li et al. (2004) identified 13 mutations in the CYP4V2 gene (see 608614.0001-608614.0006). As CYP4V2 is homologous to other members of CYP450 family 4, Li et al. (2004) suggested that it might have a role in fatty acid and steroid metabolism, which would be consistent with biochemical studies of patients with BCD (Lee et al., 2001).
In 11 unrelated patients of East Asian or Middle Eastern ancestry with BCD, Lin et al. (2005) identified homozygosity or compound heterozygosity for mutations in the CYP4V2 gene (see, e.g., 608614.0005-608614.0008).
In 4 Chinese sisters with congenital cataract, high myopia, thin corneas, and retinal findings consistent with retinitis pigmentosa, Wang et al. (2012) identified compound heterozygosity for 2 mutations in the CYP4V2 gene (608614.0005-608614.0006) that segregated fully with disease in the family. Both mutations had previously been identified in homozygosity or compound heterozygosity in patients with BCD.
In a European patient with Bietti crystalline corneoretinal dystrophy (BCD; 210370), Li et al. (2004) found compound heterozygosity for 2 mutations in the CYP4V2 gene: a 434T-A transversion in exon 1, resulting in a trp44-to-arg (W44R) mutation, and a 636T-C transition in exon 3, resulting in an ile111-to-thr mutation (I111T; 608614.0002).
For discussion of the ile111-to-thr (I111T) mutation in the CYP4V2 gene that was found in compound heterozygous state in a patient with Bietti crystalline corneoretinal dystrophy (BCD; 210370) by Li et al. (2004), see 608614.0001.
In a European patient with Bietti crystalline corneoretinal dystrophy (BCD; 210370), Li et al. (2004) identified homozygosity for an 1827G-A transition in exon 11 of the CYP4V2 gene, resulting in an arg508-to-his (R508H) mutation.
In a Chinese family, Li et al. (2004) found that Bietti crystalline corneoretinal dystrophy (BCD; 210370) was caused by compound heterozygosity for mutations in the CYP4V2 gene: a 485G-A transition in exon 1, resulting in a gly61-to-ser (G61S) mutation, and an A-to-G transition at position -2 of the acceptor splice site of intron 8 (IVS8-2A-G; 608614.0005), resulting in deletion of exon 9.
For discussion of the splice site mutation in the CYP4V2 gene (c.1091-2A-G, NM_207352.3) that was found in compound heterozygous state in patients with Bietti crystalline corneoretinal dystrophy (BCD; 210370) by Lin et al. (2005), Li et al. (2004), Wang et al. (2012), and Fu et al. (2013), see 608614.0004 and 608614.0006.
In 7 Japanese patients with Bietti crystalline corneoretinal dystrophy (BCD; 210370), Lin et al. (2005) identified homozygosity for an insertion/deletion mutation (c.802-8_810del17insGC) at intron 6 of the CYP4V2 gene that resulted in the skipping of exon 7. All 7 patients also shared homozygosity for 6 closely linked intragenic polymorphic markers, consistent with a founder effect; however, the authors noted that the founder was probably a very distant ancestor because the region of the conserved linked markers was small (6.7-17.1 kb). In a Chinese BCD patient, Lin et al. (2005) identified compound heterozygosity for this mutation and a c.992A-C transversion in the CYP4V2 gene, resulting in a his-331-to-pro (H331P; 608614.0007) substitution.
Li et al. (2004) had previously reported the indel mutation as a 15-bp deletion, which they found in homozygosity in 6 Japanese and 2 Chinese families with BCD as well as in 1 Japanese and 2 Chinese sporadic BCD patients. In addition, they identified the indel mutation in compound heterozygous state with the IVS8-2A-G mutation (608614.0005) in a Chinese patient with sporadic BCD and with the H331P mutation in affected individuals from a Chinese family. Screening for these 3 mutations in 50 controls, including 12 of Chinese, 16 of Japanese, and 22 of European origin, detected only 1 heterozygous instance of the H331P mutation in 1 Chinese control sample.
In 4 Chinese sisters with congenital cataract, high myopia, thin corneas, and a diagnosis of retinitis pigmentosa, Wang et al. (2012) identified compound heterozygosity for the c.802-8_810del17insGC mutation and the IVS8-2A-G mutation in the CYP4V2 gene. The mutations segregated fully with disease in 22 examined members of this 4-generation family.
In the proband from a Chinese family diagnosed with autosomal recessive RP, Fu et al. (2013) identified compound heterozygosity for the CYP4V2 c.802-8_810del17insGC (c.802-8_810del17insGC, NM_207352.3) and IVS8-2A-G mutations. Both mutations were also present in an affected sib, but mutation status was unknown for their unaffected deceased parents. Clinical reevaluation was not possible in this family, but reexamination of affected individuals in another Chinese RP family with mutations in CYP4V2 resulted in a rediagnosis of their phenotype as BCD (see 608614.0009).
For discussion of the c.992A-C transversion in exon 8 of the CYP4V2 gene, resulting in a his331-to-pro (H331P) substitution, that was found in compound heterozygous state in Chinese patients with Bietti crystalline corneoretinal dystrophy (BCD; 210370) by Li et al. (2004) and Lin et al. (2005), see 608614.0006.
In a 21-year-old woman and an unrelated 45-year-old man with Bietti crystalline corneoretinal dystrophy (BCD; 210370), both of Middle Eastern ancestry, Lin et al. (2005) identified homozygosity for a c.1348C-T transition in the CYP4V2 gene, resulting in a gln450-to-ter (Q450X) substitution. The mutation was not found in 90 North American controls.
In the proband from a Chinese family initially diagnosed with autosomal recessive RP but later reclassified as having Bietti crystalline corneoretinal dystrophy (BCD; 210370), Fu et al. (2013) identified compound heterozygosity for the c.802-8_810del17insGC mutation (608614.0006) and a c.1396A-G transition (c.1396A-G, NM_207352.3) in the CYP4V2 gene, resulting in an asn466-to-asp (N466D) substitution at a conserved residue. The mutations segregated with disease in the family. Reexamination of affected family members revealed the characteristic yellowish shiny crystals of BCD in the proband's younger sister, although none were observed in the proband. Fu et al. (2013) stated that in their experience, the crystals seen in BCD may vanish as patients age and the disease progresses; they thus clinically rediagnosed this family with BCD.
Fu, Q., Wang, F., Wang, H., Xu, F., Zaneveld, J. E., Ren, H., Keser, V., Lopez, I., Tuan, H.-F., Salvo, J. S., Wang, X., Zhao, L., Wang, K., Li, Y., Koenekoop, R. K., Chen, R., Sui, R. Next-generation sequencing-based molecular diagnosis of a Chinese cohort with autosomal recessive retinitis pigmentosa. Invest. Ophthal. Vis. Sci. 54: 4158-4166, 2013. [PubMed: 23661369] [Full Text: https://doi.org/10.1167/iovs.13-11672]
Jiao, X., Munier, F. L., Iwata, F., Hayakawa, M., Kanai, A., Lee, J., Schorderet, D. F., Chen, M.-S., Kaiser-Kupfer, M., Hejtmancik, J. F. Genetic linkage of Bietti crystallin corneoretinal dystrophy to chromosome 4q35. Am. J. Hum. Genet. 67: 1309-1313, 2000. [PubMed: 11001583] [Full Text: https://doi.org/10.1016/S0002-9297(07)62960-7]
Lee, J., Jiao, X., Hejtmancik, J. F., Kaiser-Kupfer, M., Gahl, W. A., Markello, T. C., Guo, J., Chader, G. J. The metabolism of fatty acids in human Bietti crystalline dystrophy. Invest. Ophtal. Vis. Sci. 42: 1707-1714, 2001.
Li, A., Jiao, X., Munier, F. L., Schorderet, D. F., Yao, W., Iwata, F., Hayakawa, M., Kanai, A., Chen, M. S., Lewis, R. A., Heckenlively, J., Weleber, R. G., Traboulsi, E. I., Zhang, Q., Xiao, X., Kaiser-Kupfer, M., Sergeev, Y. V., Hejtmancik, J. F. Bietti crystalline corneoretinal dystrophy is caused by mutations in the novel gene CYP4V2. Am. J. Hum. Genet. 74: 817-826, 2004. [PubMed: 15042513] [Full Text: https://doi.org/10.1086/383228]
Lin, J., Nishiguchi, K. M., Nakamura, M., Dryja, T. P., Berson, E. L., Miyake, Y. Recessive mutations in the CYP4V2 gene in East Asian and Middle Eastern patients with Bietti crystalline corneoretinal dystrophy. J. Med. Genet. 42: e38, 2005. Note: Electronic Article. [PubMed: 15937078] [Full Text: https://doi.org/10.1136/jmg.2004.029066]
Wang, Y., Guo, L., Cai, S.-P, Dai, M., Yang, Q., Yu, W., Yan, N., Zhou, X., Fu, J., Guo, X., Han, P., Wang, J., Liu, X. Exome sequencing identifies compound heterozygous mutations in CYP4V2 in a pedigree with retinitis pigmentosa. PLoS One 7: e33673, 2012. Note: Electronic Article. [PubMed: 22693542] [Full Text: https://doi.org/10.1371/journal.pone.0033673]