Dataset Information

Recessive mutations in the CYP4V2 gene in East Asian and Middle Eastern patients with Bietti crystalline corneoretinal dystrophy.

ABSTRACT: Bietti crystalline corneoretinal dystrophy (BCD) is an autosomal recessively inherited disorder characterised by tiny yellowish glittering retinal crystals, choroidal sclerosis, and crystals in the peripheral cornea, associated with progressive night blindness. CYP4V2, encoding a member of cytochrome p450 (CYP450) protein family, was recently identified as the causative gene.We recruited 11 unrelated patients with BCD and characteristic clinical features; eight of Japanese, two of Middle Eastern, and one of Chinese ancestry. Genomic DNA was extracted from peripheral blood leucocytes, and all 11 exons and the flanking intron splice sites of the CYP4V2 gene were amplified and sequenced. A complete ophthalmological examination was performed.We found recessive mutations in the CYP4V2 gene in all of the 11 patients. Two novel mutations, L173W and Q450X, were identified in a Japanese patient and two unrelated patients from Middle Eastern countries, respectively. Each patient was a homozygote. A previously reported mutation IVS6-8_810delinsGC was identified in seven unrelated Japanese patients and the Chinese patient with BCD. All patients with BCD shared a characteristic fundus appearance with numerous intraretinal crystal deposits and atrophy of the retinal pigment epithelium. However, the clinical findings, including elecroretinograph recordings, indicated that there was considerable variation in the degree of visual dysfunction even among patients of similar ages carrying the same mutation.Defects in CYP4V2 are the main cause of BCD. The IVS6-8_810delinsGC mutant allele may be especially prevalent among patients with BCD in East Asian countries, resulting from a single founder. Variation of disease severity suggests that environmental or additional genetic factors influence the course of the retinal disease.

SUBMITTER: Lin J

PROVIDER: S-EPMC1736086 | biostudies-other | 2005 Jun

REPOSITORIES: biostudies-other

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Recessive mutations in the CYP4V2 gene in East Asian and Middle Eastern patients with Bietti crystalline corneoretinal dystrophy.

Lin J J Nishiguchi K M KM Nakamura M M Dryja T P TP Berson E L EL Miyake Y Y

Journal of medical genetics 20050601 6

<h4>Background</h4>Bietti crystalline corneoretinal dystrophy (BCD) is an autosomal recessively inherited disorder characterised by tiny yellowish glittering retinal crystals, choroidal sclerosis, and crystals in the peripheral cornea, associated with progressive night blindness. CYP4V2, encoding a member of cytochrome p450 (CYP450) protein family, was recently identified as the causative gene.<h4>Methods</h4>We recruited 11 unrelated patients with BCD and characteristic clinical features; eight ...[more]

PMID: 15937078

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Project description:BackgroundIt is not clear how lay people prioritize the various, sometimes conflicting, interests when they make surrogate medical decisions, especially in non-Western cultures. The extent such decisions are perspective-related is also not well documented.MethodsWe explored the relative importance of 28 surrogate decision-making factors to 120 Middle-Eastern (ME) and 120 East-Asian (EA) women from three perspectives, norm-perception (N), preference as patient (P), and preference as surrogate decision-maker (S). Each respondent force-ranked (one to nine) 28 opinion-items according to each perspective. Items' ranks were analyzed by averaging-analysis and Q-methodology.ResultsRespondents' mean (SD) age was 33.2 (7.9) years; all ME were Muslims, 83% of EA were Christians. "Trying everything possible to save patient," "Improving patient health," "Patient pain and suffering," and/or "What is in the best interests of patient" were the three most-important items, whereas "Effect of caring for patient on all patients in society," "Effect of caring for patient on patients with same disease," and/or "Cost to society from caring for patient" were among the three least-important items, in each ME and EA perspectives. P-perspective assigned higher mean ranks to family and surrogate's needs and burdens-related items, and lower mean rank to "Fear of loss" than S-perspective (p<0.001). ME assigned higher mean ranks to "Medical facts" and "Surrogate own wishes for patient" and lower mean rank to "Family needs" in all perspectives (p<0.001). Q-methodology identified models that were relatively patient's preference-, patient's religious/spiritual beliefs-, or emotion-dependent (all perspectives); medical facts-dependent (N- and S-perspectives), financial needs-dependent (P- and S-perspectives), and family needs-dependent (P-perspective).Conclusions1) Patient's health was more important than patient's preference to ME and EA women; society interest was least important. 2) Family and surrogate's needs/ burdens were more important, whereas fear of loss was less important to respondents as patients than as surrogate decision-makers. 3) Family needs were more important to EA than ME respondents, the opposite was true for medical facts and surrogate's wishes for patient. 4) Q-methodology models that relatively emphasized various surrogate decision-making factors overlapped the ME and EA women' three perspectives.

Project description:To characterize the spectrum of CYP4V2 gene mutations in 92 unrelated Chinese probands with Bietti's crystalline dystrophy (BCD) and to describe the molecular and clinical characteristics of four novel CYP4V2 mutations associated with BCD.All study participants underwent a complete ophthalmological examination. Mutational screening of CYP4V2 coding regions and flanking intron sequences was examined via directional Sanger sequencing, with allele separation confirmed by screening other family members. Subsequent in silico analysis of the mutational consequence on protein function was undertaken, with the impact of the novel mutation on pre-mRNA splicing examined via RT-PCR.Fifteen disease-causing variants were identified in 92 probands with BCD, including four novel mutations and eleven previously reported mutations. The most prevalent mutation was c.802_810del17insGC, which was detected in 69 unrelated families, with an allele frequency of 52.7% (97/184). Homozygosity was revealed in 35 unrelated families, and compound heterozygosity was observed in 43 subjects. Four patients harbored four novel variants, with these mutations cosegregated within all affected individuals and were not found in unaffected family members and 100 unrelated controls. Transcriptional analysis of a novel splice mutation revealed altered RNA splicing. In silico analysis predicted that the missense variant, p.Tyr343Asp, disrupted the CYP4V2 surface electrostatic potential distribution and spatial conformation. Among the patients with four novel mutations, genotype did not always correlate with age at onset, disease course, or electroretinogram (ERG) changes, with phenotypic variations even noted within the same genotype.The c.802_810del17insCG mutation was the most common mutation in the 92 Chinese probands with BCD examined. Four novel mutations were identified, contributing to the spectrum of CYP4V2 mutations associated with BCD, with no clear link established between disease phenotype and genotype.

Dataset Information

Recessive mutations in the CYP4V2 gene in East Asian and Middle Eastern patients with Bietti crystalline corneoretinal dystrophy.

Publications

Recessive mutations in the CYP4V2 gene in East Asian and Middle Eastern patients with Bietti crystalline corneoretinal dystrophy.

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