Bietti Crystalline Corneoretinal Dystrophy Is Caused by Mutations in the Novel Gene CYP4V2

Abstract

Bietti crystalline corneoretinal dystrophy (BCD) 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. The BCD region of chromosome 4q35.1 was refined to an interval flanked centromerically by D4S2924 by linkage and haplotype analysis; mutations were found in the novel CYP450 family member CYP4V2 in 23 of 25 unrelated patients with BCD tested. The CYP4V2 gene, transcribed from 11 exons spanning 19 kb, is expressed widely. Homology to other CYP450 proteins suggests that CYP4V2 may have a role in fatty acid and steroid metabolism, consistent with biochemical studies of patients with BCD.

Identification and population history of CYP4V2 mutations in patients with Bietti crystalline corneoretinal dystrophy

“…Although the number of mutations identified in this study and Li et al, 5 40, is relatively small, some patterns do emerge when the ethnicity of the patients displaying those mutations is examined, especially the more common mutations. Of the 99 combined unrelated patients and families examined, the ethnicity of 13 of them was unknown, leaving 86: 31 of European origin, 38 of Chinese origin, 1 of Arabic origin, 8 of Korean origin, and 8 of Japanese origin (Table 3).…”

“…included in this study were aligned along with those from Li et al, 5 Lin et al, 22 and Lee et al 23 as shown in Figure 2. The CAAT(delCT)TA (indel)TCA haplotype shaded in dark blue in homozygotes was the most common in Chinese, Japanese, and Koreans, and was assumed to be the ancestral haplotype for all three population groups.…”

“…4 Sequence variants that affect the function of CYP4V2 (MIM 608614), a member of the heme thiolate cytochrome P450 subfamily 4 (CYP4), predominantly active in fatty acid metabolism, cause BCD. 5 The CYP4V2 gene spans 21 kb, comprising 11 exons encoding a 525 amino acid protein (Figure 1, top). Although CYP4V2 is expressed in almost all tissues, it is expressed at high levels in the retina and RPE, and at somewhat lower levels in the cornea tissues, which show the major clinical findings of BCD.…”

“…Although CYP4V2 is expressed in almost all tissues, it is expressed at high levels in the retina and RPE, and at somewhat lower levels in the cornea tissues, which show the major clinical findings of BCD. 5 CYP4V2 is a PUFA hydroxylase highly expressed P450 in the transformed human RPE cell line ARPE-19. 6 Consistent with this, abnormalities in ω3-PUFAs and their metabolism have been demonstrated in patients with BCD.…”

“…5 PCR products were purified using Agencourt CleanSEQ (Beckman Coulter, Biomek NX, Brea, CA, USA). Sequencing was performed on an ABI PRISM 3130 Automated sequencer (Applied Biosystems, Foster City, CA, USA) and analyzed using Mutation Surveyor v3.30 (Soft Genetics, State College, PA, USA) or Lasergene 8.0, (DNASTAR, Madison, WI, USA).…”