Identification of CYP4V2 mutation in 21 families and overview of mutation spectrum in Bietti crystalline corneoretinal dystrophy

State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, PR China.
Biochemical and Biophysical Research Communications (Impact Factor: 2.3). 06/2011; 409(2):181-6. DOI: 10.1016/j.bbrc.2011.04.112
Source: PubMed


Bietti crystalline corneoretinal dystrophy (BCD, MIM 210370) is a common form of hereditary retinal degeneration in the Chinese population. BCD is caused by CYP4V2 mutations. Understanding the CYP4V2 mutational spectrum and associated phenotypes is of value for clinical practice. In this study, nine CYP4V2 mutations, including four novel ones (c.215-2A>G, c.761A>G, c.958C>T, and c.1169G>A), were detected in all 21 families with BCD. All patients with CYP4V2 mutations had phenotypes typical for BCD. As of now, 34 CYP4V2 mutations have been identified in 104 of 109 families (95.4%), affecting 204 of the 218 alleles (93.6%). Of the 34 mutations, c.802-8_810del17insGC, c.992A>C, and c.1091-2A>G are the most common mutations, accounting for 62.7%, 7.4%, and 6.4% of the 204 mutant alleles, respectively. The remaining 31 mutations were only detected in 1-6 alleles. Mutations in exons 7, 8, and 9 account for 83.3% of mutant alleles (64.7%, 9.3%, and 10.3%, respectively). Our results expand the mutation spectrum of CYP4V2 and demonstrate an overview of the CYP4V2 mutation spectrum and its frequency in families with BCD. BCD is a clinically and genetically homogenous disease.

Download full-text


Available from: Qingjiong Zhang, Mar 20, 2015
  • Source
    • "The causative gene for BCD, CYP4V2 (MIM 608614), has been identified in chromosome 4q35.1 by Li and colleagues [2], [9]. To date, more than 50 mutations of CYP4V2 have been identified in patients with BCD [8], [10], [11], [12], [13], [14], [15], [16]. CYP4V2 is a member of the cytochrome P450 heme thiolate protein superfamily and may be the dominant functional CYP4 enzyme in disease-targeted ocular tissues of BCD, such as RPE and corneal epithelium [17]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: To investigate the clinical features and cytochrome P450 family 4 subfamily V polypeptide 2 (CYP4V2) gene mutations in 14 Chinese families with Bietti crystalline dystrophy (BCD). Seventeen patients from 14 unrelated Chinese families with BCD were recruited for complete clinical ophthalmic examination and genetic study. The 11 exons of CYP4V2 were amplified from genomic DNA of all patients and their family members by polymerase chain reaction (PCR) and then sequenced. Exons of TIMP3 were also sequenced in BCD patient associated with choroidal neovascularization (CNV). One hundred and seventy unrelated healthy Chinese subjects were screened for mutations in CYP4V2. All 17 patients with BCD had mutations in CYP4V2; one of these mutations was novel (c.219T>A, p.F73L) and four other mutations had been reported. The p.F73L mutation was a commonly detected mutation in our study (seven out of 34 alleles), either in the homozygous state or in the heterozygous state. Among the patients, considerable phenotypic variability was detected, both within and between families. Screening of TIMP3 did not find any mutation in the BCD patient associated with CNV. The novel CYP4V2 c.219T>A (p.F73L) mutation may be another recurrent mutation in Chinese patients with BCD. Our study expands the mutation spectrum of CYP4V2 and characterizes novel genotype-phenotype associations in Chinese patients with BCD.
    Full-text · Article · Apr 2014 · PLoS ONE
  • Source
    • "The gene responsible for BCD, CYP4V2, is expressed widely in human heart, brain, placenta, lung, liver, retina and RPE. To date, 39 mutations of CYP4V2 have been described in patients with BCD.8–13 This gene codes for a protein whose structure suggests that it may be active in fatty acid metabolism. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Aim The aim of the study was to describe the clinical and genetic features of 15 Italian patients with Bietti crystalline dystrophy (BCD). Methods All study participants underwent a complete ophthalmological examination, including standard electroretinogram (ERG), optical coherence tomography, microperimetry, autofluorescence and multifocal electroretinogram. The 11 exons of the CYP4V2 gene were sequenced. The effect of mutations on protein function was estimated by a combination of web based programs. Results 15 patients (eight women, 7 men, aged 29–60 years) with BCD were recruited into this study. Sequencing of CYP4V2 revealed nine sequence variants in four unrelated families and six isolated individuals with BCD. Seven of these variants were novel. Among the patients, even with the same genotype, considerable variability in phenotypic expression with different degrees of accumulation of the typical intraretinal crystalline deposits was detected. Moreover, we found that more than 50% of patients had recordable standard ERG responses and in two patients the responses were within normal limits after 20 years of symptom onset. Conclusions In conclusion, we have reported seven new mutations and illustrated the large range of genotypic and phenotypic variability in BCD, highlighting the lack of a clear genotype–phenotype correlation and underlining the existence of less severe clinical manifestations, probably linked to relatively mild mutations.
    Full-text · Article · Dec 2012 · The British journal of ophthalmology
  • Source
    • "6 to 9 account for Ͼ80% of all mutations, with at least three founder mutations (i.e., c.802-8_810del17insGC, c.992AϾC, and c.1091-2AϾG, accounting for 62.7, 7.4, and 6.4%, respectively of all mutated alleles) (Xiao et al., 2011). Although complex lipid deposits are also found in the circulating lymphocytes and skin fibroblasts of patients with BCD (Wilson et al., 1989; Kaiser-Kupfer et al., 1994) and expression of CYP4V2 mRNA has been detected in most human tissues (Li et al., 2004), the clinical disease phenotype seems to be restricted to the eye. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Bietti's crystalline corneoretinal dystrophy (BCD) is a recessive degenerative eye disease caused by germline mutations in the CYP4V2 gene. More than 80% of mutant alleles consist of three mutations, that is, two splice-site alterations and one missense mutation, c.992C>A, which translates to p.H331P. In the present study, we analyzed the expression of CYP4 family members in human tissues and conducted functional studies with the wild-type and p.H331P enzymes, to elucidate the link between CYP4V2 activity and BCD. Expression analysis of 17 CYP1 to CYP4 genes showed CYP4V2 to be a major cytochrome P450 in ARPE-19 cells (a human cell line spontaneously generated from normal human retinal pigmented epithelium) and the only detectable CYP4 transcript. Immunohistochemical analyses demonstrated that CYP4V2 protein was present in epithelial cells of the retina and cornea and the enzyme was localized to endoplasmic reticulum. Recombinant reconstituted CYP4V2 protein metabolized eicosapentaenoic acid and docosahexaenoic acid (an important constituent of the retina) to their respective ω-hydroxylated products at rates similar to those observed with purified CYP4F2, which is an established hepatic polyunsaturated fatty acid (PUFA) hydroxylase. The disease-associated p.H331P variant was undetectable in Western blot analyses of HepG2 cells stably transduced with lentiviral expression vectors. Finally, overexpression of functional CYP4V2 in HepG2 cells altered lipid homeostasis. We demonstrated that CYP4V2 protein is expressed at high levels in ocular target tissues of BCD, that the enzyme is metabolically active toward PUFAs, and that the functional deficit among patients with BCD who carry the H331P variant is most likely a consequence of the instability of the mutant protein.
    Full-text · Article · Jul 2012 · Molecular pharmacology
Show more