Molecular Analysis and Phenotypic Study in 14 Chinese Families with Bietti Crystalline Dystrophy

Yin, Houfa; Jin, Chao; Fang, Xiaoyun; Miao, Qi; Zhao, Yingying; ZhiQing, Chen; Su, Zhaoan; Ye, Panpan; Wang, Yao; Yin, Jinfang

doi:10.1371/journal.pone.0094960

Cited by 28 publications

(26 citation statements)

References 33 publications

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“…17 Cystoid macular edema has also been observed in a few reported cases of BCD. 17,26,36 Fundus Autofluorescence Findings Fundus autofluorescence (FAF) imaging with confocal scanning laser ophthalmoscope imaging is derived from lipofuscin within the RPE, allowing noninvasive visualization of the RPE layer in BCD patients. 35 In the early stage of BCD, FAF reveals widespread hypoautofluorescence corresponding to areas of RPE atrophy and multiple hyperautofluorescent speckles in the fundus (Fig.…”

Section: Fundus and Anterior Segment Features Of Bcdmentioning

confidence: 99%

“…49,55 Interestingly, clinical symptoms of BCD remain only in the eyes. The link between altered 32 Yin et al, 36 Meng et al, 59 Manzouri et al, 64 Shan et al 60 15 3 c.332T>C p.I111T Missense Li et al, 55 Astuti et al, 63 Rossi et al, 61 García-García et al, 65 Haddad et al, 66 Rossi et al 67 10 Lin et al, 11 Li et al, 17 Gocho et al, 27 Halford et al, 32 Yin et al, 36 Li et al, 55 Xiao et al, 57 Meng et al, 59 Astuti et al, 63 Nakamura et al, 68 Lee et al, 69 Chung et al, 70 Gekka et al, 71 Jin et al, 72 Liu et al, 73 Shan et al, 60 Tian et al, 62 Wada et al, 74 10 Li et al, 17 Li et al, 55 Xiao et al, 57 Meng et al, 59 36 Meng et al, 59 Mamatha et al 77 43 9 c.1091-2A>G Exon9del Splice site Li et al, 17 Yin et al, 36 Li et al, 55 Xiao et al, 57 Meng et al, 59 Shan et a...…”

Section: Role Of Cyp4v2 In Fatty Acid Metabolismmentioning

confidence: 99%

“…55 Around 60 mutations in the CYP4V2 gene have now been described in individuals with BCD (Table 1). 10,11,17,27,32,36,55,57, At least 1 pathogenic variant has been reported in each of the 11 exons of CYP4V2. The most common mutation observed in BCD is the insertion-deletion mutation at intron 6-exon 7 junction (IVS6-8del17bp/insGC or c.802-8del17bp/insGC).…”

Section: Known Mutations For Bcdmentioning

confidence: 99%

“…10,32,36,61,63,69 Our group has previously evaluated the genotype-phenotype correlation in a group of 18 Chinese patients in 13 families and showed that BCD with homozygous IVS6-8del17bp/insGC (c.802-8del17bp/insGC) or compound heterozygous IVS6-8del17bp/insGC and IVS8-2A_G (c1091-2A>G) mutations seemed to have a more severe disease phenotype based on electrophysiological testing. 10 Deletion at the exon 7 splice acceptor site causes an in-frame deletion of exon 7, resulting in the expression of a truncated protein.…”

Section: Genotype and Phenotype Correlation In Bcdmentioning

confidence: 99%

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Genetics of Bietti Crystalline Dystrophy

Ng¹,

Lai²,

Ng³

et al. 2016

Asia-Pacific Journal of Ophthalmology

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Bietti crystalline dystrophy (BCD) is an inherited retinal degenerative disease characterized by crystalline deposits in the retina, followed by progressive atrophy of the retinal pigment epithelium (RPE), choriocapillaris, and photoreceptors. CYP4V2 has been identified as the causative gene for BCD. The CYP4V2 gene belongs to the cytochrome P450 superfamily and encodes for fatty acid ω-hydroxylase of both saturated and unsaturated fatty acids. The CYP4V2 protein is localized most abundantly within the endoplasmic reticulum in the RPE and is postulated to play a role in the physiological lipid recycling system between the RPE and photoreceptors to maintain visual function. Electroretinographic assessments have revealed progressive dysfunction of rod and cone photoreceptors in patients with BCD. Several genotypes have been associated with more severe phenotypes based on clinical and electrophysiological findings. With the advent of multimodal imaging with spectral domain optical coherence tomography, fundus autofluorescence, and adaptive optics scanning laser ophthalmoscopy, more precise delineation of BCD severity and progression is now possible, allowing for the potential future development of targets for gene therapy.

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Section: Fundus and Anterior Segment Features Of Bcdmentioning

confidence: 99%

Section: Role Of Cyp4v2 In Fatty Acid Metabolismmentioning

confidence: 99%

Section: Known Mutations For Bcdmentioning

confidence: 99%

Section: Genotype and Phenotype Correlation In Bcdmentioning

confidence: 99%

See 2 more Smart Citations

Genetics of Bietti Crystalline Dystrophy

Ng¹,

Lai²,

Ng³

et al. 2016

Asia-Pacific Journal of Ophthalmology

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“…Although it is theoretically possible that mutations in a different gene can cause BCD in these cases, no other Table 4 Mutation age estimates of the c.802-510 8_810del17insGC indel mutation in the Chinese and Japanese populations Method rs7663027 rs10013653 rs7682918 rs12507156 rs397722245 rs4862662 rs13146272 * rs28698123 rs7667777 rs2276918 gene or linkage region has been suggested in multiple previous studies, many of which include linkage data, and two mutations have been found in~92% of BCD patients. 5,[22][23][24][26][27][28][29][30][31][32][33][34] The c.802-8_810del17insGC change, the most common mutation of CYP4V2 in East Asian BCD patients, was found in 15 cases of 58 BCD patients in this study, all of East Asian origin. Overall, we have found the c.802-8_810del17insGC change in 14 individuals of Chinese, 1 of Japanese and 4 of Korean origin, 5 consistent with estimates from the 1000 Genomes database, in which the allele frequency of this mutation is 0.01 in Japan and 0.005 in China, but only 0.002 in Europe and was not seen in African, South Asian, or American populations.…”

Section: Discussionmentioning

confidence: 95%

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

Jiao

Jin

et al. 2017

Eur J Hum Genet

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To identify known and novel CYP4V2 mutations in patients with Bietti crystalline cornea (BCD), expand the spectrum of CYP4V2 mutations, and characterize the population history of the c.802-8_810del17insGC mutation common in Asian populations, genomic DNA was isolated from peripheral blood samples from 58 unrelated patients with clinical diagnoses of BCD. Exons and flanking intronic regions of the CYP4V2 gene were dideoxy DNA sequenced. Nonpathogenic polymorphisms were excluded and known mutations were identified by sequencing 192 unaffected individuals from similar ethnic backgrounds and examination of online databases. The age of the c.802-8_810del17insGC mutation was estimated using three independent approaches. A total of 28 CYP4V2 mutations, 9 of which were novel, were detected in the 58 patients with BCD. These included 19 missense, 4 nonsense, 2 deletion, 2 splice site, and 1 insertion-deletion mutations. Two missense variants of uncertain significance were also detected. The age of the c.802-8_810del17insGC mutation was estimated to be 1040-8200 generations in the Chinese and 300-1100 generations in the Japanese populations. These results expand the mutation spectrum of CYP4V2, and provide insight into the origin of the c.802-8_810del17insGC mutation in the Chinese population and its transmission to the Japanese population.

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Novel insights into the molecular pathogenesis ofCYP4V2‐associated Bietti's retinal dystrophy

Astuti

Sun

Bauwens

et al. 2014

Mol Genet Genomic Med

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Bietti's crystalline dystrophy (BCD) is a rare, autosomal recessive retinal degenerative disease associated with mutations in CYP4V2. In this study, we describe the genetic and clinical findings in 19 unrelated BCD patients recruited from five international retinal dystrophy clinics. Patients underwent ophthalmic examinations and were screened for CYP4V2 mutations by Sanger sequencing and quantitative polymerase chain reaction (qPCR) copy number variation screening. Eight CYP4V2 mutations were found in 10/19 patients, including three patients in whom only monoallelic mutations were detected. Four novel mutations were identified: c.604G>A; p.(Glu202Lys), c.242C>G; p.(Thr81Arg), c.604+4A>G; p.(?), and c.1249dup; p.(Thr417Asnfs*2). In addition, we identified a heterozygous paternally inherited genomic deletion of at least 3.8 Mb, encompassing the complete CYP4V2 gene and several other genes, which is novel. Clinically, patients demonstrated phenotypic variability, predominantly showing choroidal sclerosis, attenuated vessels, and crystalline deposits of varying degrees of severity. To our knowledge, our study reports the first heterozygous CYP4V2 deletion and hence a novel mutational mechanism underlying BCD. Our results emphasize the importance of copy number screening in BCD. Finally, the identification of CYP4V2-negative patients with indistinguishable phenotypes from CYP4V2-positive patients might suggest the presence of mutations outside the coding regions of CYP4V2, or locus heterogeneity, which is unreported so far.

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Molecular Analysis and Phenotypic Study in 14 Chinese Families with Bietti Crystalline Dystrophy

Cited by 28 publications

References 33 publications

Genetics of Bietti Crystalline Dystrophy

Genetics of Bietti Crystalline Dystrophy

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

Novel insights into the molecular pathogenesis ofCYP4V2‐associated Bietti's retinal dystrophy

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