<i>CYP4V2</i> Mutations in Two Japanese Patients with Bietti’s Crystalline Dystrophy

Abstract

Bietti’s crystalline dystrophy (BCD) is an autosomal-recessive retinal dystrophy characterized by numerous glistening intraretinal dots scattered over the fundus, particularly in the posterior pole. The purpose of this study was to report mutations in the CYP4V2 gene (encoding a ubiquitously-expressed 525-amino acid sequence belonging to the CYP450 family) and to investigate the impact of the mutation on pre-mRNA splicing. DNA and RNA analyses were conducted using blood samples from two unrelated Japanese patients with BCD (a 46-year-old female and a 52-year-old male). In the female patient, a homozygous deletion/insertion mutation (g.IVS6–8_–1delc.802_810del/insGC) including the 3´-acceptor splice site was identified. Reverse transcription-PCR analysis revealed that the complete length of exon 7 (186 bp), is skipped, resulting in the in-frame deletion mutation (p.V268_E329del). Conversely, the male patient was a compound heterozygote for the deletion/insertion and novel nonsense (p.W340X) mutations. Clinically, the female patient had decreased visual acuity, constriction of visual fields, severely reduced amplitudes in both rod and cone electroretinograms (ERGs). Despite being 6 years older, the male patient presented with milder clinical manifestations having good visual acuity and substantial amplitudes in both rod and cone ERGs. Because the CYP4V2 truncated protein with the p.W340X mutation lacks 186 amino acids at the C-terminus, if expressed, it retains 62 amino acids encoded in exon 7, which are important for enzymatic activity. In the male patient, expression of both mutant alleles may compensate for the malfunction of each mutated protein and could explain why a milder form of BCD results from compound heterozygosity.

CYP4V2 in Bietti's Crystalline Dystrophy: Ocular Localization, Metabolism of ω-3-Polyunsaturated Fatty Acids, and Functional Deficit of the p.H331P Variant

“…After the genetic defect was initially linked to chromosome 4q35 (Jiao et al, 2000), Li et al (2004) identified biallelic mutations in the "orphan" P450 enzyme CYP4V2 in 23 of 25 index patients from families with BCD. Numerous research groups (Gekka et al, 2005;Lin et al, 2005;Shan et al, 2005;Wada et al, 2005;Yokoi et al, 2010) confirmed the original genetic findings (Kelly et al, 2011). A recent study demonstrated that more than 95% of all patients with BCD for whom analyses were performed had germline mutations in the CYP4V2 gene (Xiao et al, 2011).…”

Bietti’s crystalline dystrophy in Asians: clinical, angiographic and electrophysiological characteristics

“…More recently, the area of genetic analysis has borne many exciting discoveries. Li et al [22,23] mapped the BCD gene locus to chromosome 4q35.1, and a variety of mutations involving the CYP4V2 gene has since been identified [4,[24][25][26][27]. The CYP4V2 gene is a novel member of the cytochrome P450 group of genes, and it codes for a 525-amino-acid protein active in fatty acid metabolism.…”

Novel CYP4V2 Gene Mutation in a Mexican Patient with Bietti's Crystalline Corneoretinal Dystrophy

“…4,11 Genetic linkage analysis in several BCD families established 4q35-qter as the chromosomal segment harboring the putative causal gene 12 and mutations in CYP4V2 (for cytochrome P450, family 4, subfamily V, polypeptide 2), a gene located within this region, were subsequently identified in a number of patients with the disease. 7,8,13,14 CYP4V2 is composed of 11 exons that encode a widely expressed 525 amino acid CYP450 family member, which is presumably involved in fatty acid metabolism. 7 Approximately 23 different CYP4V2 mutations have been described to date, predominantly in patients from Asia.…”