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      CYP4V2 Mutations in Two Japanese Patients with Bietti’s Crystalline Dystrophy

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          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.

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          Most cited references 13

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          Mutation nomenclature extensions and suggestions to describe complex mutations: a discussion.

          Consistent gene mutation nomenclature is essential for efficient and accurate reporting, testing, and curation of the growing number of disease mutations and useful polymorphisms being discovered in the human genome. While a codified mutation nomenclature system for simple DNA lesions has now been adopted broadly by the medical genetics community, it is inherently difficult to represent complex mutations in a unified manner. In this article, suggestions are presented for reporting just such complex mutations. Copyright 2000 Wiley-Liss, Inc.
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            Bietti crystalline corneoretinal dystrophy is caused by mutations in the novel gene CYP4V2.

            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.
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              Bietti's crystalline corneoretinal dystrophy: a cross-sectional study.

              To evaluate the prevalence of Bietti's corneoretinal dystrophy (BCD) in a reference population of retinitis pigmentosa (RP), and to document the disease course clinically and angiographically by a cross-sectional approach. Two hundred seven consecutive RP patients were ascertained within a 3-year period. All patients had a complete eye examination, including fluorescein and indocyanine green angiography (FA, ICG). Blood samples were collected for electron microscopy evaluation of circulating lymphocytes of BCD patients. Six patients were diagnosed with BCD. Prevalence was 3% of nonsyndromic RP cases. Limbal corneal and intraretinal crystals were found in all cases. In the early phase of BCD, ICG revealed focal lobular areas of choriocapillary atrophy at the equator, with concomitant retinal pigment epithelium (RPE) changes at the posterior pole on FA. These lesions gradually progressed both anteriorly and posteriorly, sparing an incomplete peripapillary ring and macular island until late in the disease. Progressive sclerosis of ciliary and choroidal arteries was noted upon ICG. The presence of lysosomal crystals was documented in a subpopulation of circulating lymphocytes that seemed to increase with age. The present study is the first to assess BCD prevalence in a population of retinitis pigmentosa patients, to describe clinically and angiographically its evolution from first symptom to legal blindness, and to localize the first fundus alterations not only at the posterior pole but also at the equator.

                Author and article information

                Ophthalmic Res
                Ophthalmic Research
                S. Karger AG
                October 2005
                15 September 2005
                : 37
                : 5
                : 262-269
                Department of Ophthalmology, Jikei University School of Medicine, Tokyo, Japan
                87214 Ophthalmic Res 2005;37:262–269
                © 2005 S. Karger AG, Basel

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                Page count
                Figures: 6, References: 29, Pages: 8
                Original Paper


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