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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: 2.28). 06/2011; 409(2):181-6. DOI: 10.1016/j.bbrc.2011.04.112
Source: PubMed

ABSTRACT 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.

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    • "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. "
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    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.
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    ABSTRACT: Purpose: To describe the clinical and genetic characteristics of a Japanese family in which one member exhibited Bietti's crystalline corneoretinal dystrophy (BCD). Methods: Using direct sequencing, mutation screening was performed in the CYP4V2 gene of both the patient with BCD and her daughter. Ophthalmic examinations were performed to determine the clinical features of both subjects. Results: The 64-year-old female patient had a bilateral visual acuity of 0.4. Slit lamp examination revealed bilateral crystalline-like deposits at the superior limbus of the cornea. Fundus examination revealed there was chorioretinal atrophy along with numerous glistening yellowish-white crystalline deposits that were scattered throughout the posterior pole and the mid-peripheral retina. Standard flash electroretinography showed an extinguished electroretinogram and Goldmann kinetic perimetry detected a relative scotoma. Genetic analysis revealed that the patient had a heterozygous mutation in the CYP4V2 gene (IVS6-8delTCATACAGGTCATCGCG/GC), which is the most commonly found mutation in Japanese patients with BCD. Furthermore, the patient was also shown to have a novel heterozygous point mutation in exon 9 of the CYP4V2 gene (c.1168C>T). In contrast, her daughter exhibited no clinical findings for BCD even though she carried the same heterozygous mutation in the CYP4V2 gene (c.1168C>T). Conclusion: A novel compound heterozygous mutation was found in the CYP4V2 gene of a patient with BCD. This previously unreported c.1168C>T mutation causes a missense mutation (p.R390C) in the CYP4V2 protein.
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    ABSTRACT: Bietti crystalline dystrophy (BCD) is a rare autosomal recessive disorder caused by mutation of the cytochrome P450, family 4, subfamily V, polypeptide 2 (CYP4V2) gene and characterized by retinal pigmentary abnormalities and scattered deposits of crystals in the retina and the marginal cornea. The aim of this study was to investigate the spectrum of mutations in CYP4V2 in Lebanese families, and to characterize the phenotype of patients affected with BCD. Nine patients from three unrelated Lebanese families were clinically and molecularly investigated. Detailed characterization of the patients' phenotype was performed with comprehensive ophthalmic examination, color vision study, fundus photography, visual field testing, retinal fluorescein angiography, electroretinography, and electrooculography. One family was followed for 12 years. The 11 exons of the CYP4V2 gene were sequenced. Symptoms consisting of night blindness, loss of paracentral visual field, and disturbed color vision were apparent during the third decade of life. Ophthalmoscopy revealed posterior pole crystalline deposits and areas of retinal pigment epithelium atrophy. Fluorescein angiography disclosed geographic areas of the pigment epithelium layer and choriocapillaris atrophy in the posterior pole and fundus periphery. The most striking findings were those of normal electroretinographic responses in some patients and clinical heterogeneity. Two mutations in CYP4V2 were found: p.I111T (c.332T>C) in exon 3 in two families and the novel p.V458M (c.1372G>A) mutation in exon 9 in one family. These patients are affected with Bietti crystalline dystrophy without corneal involvement. Variation in disease severity and electroretinographic responses suggests that environmental or additional genetic factors influence the course of the retinal disease. The CYP4V2 p.I111T (c.332T>C) mutant allele may be especially prevalent among patients with BCD in Lebanon, resulting from a single founder.
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