Bietti Crystalline Corneoretinal Dystrophy is caused by mutations in the novel gene CYP4V2, a new member of the Cytochrome P450

Abstract

Abstract: : Purpose:Bietti crystalline corneoretinal dystrophy (BCD) is an autosomal recessive retinal degeneration. We have previously mapped BCD to a locus on chromosome 4q35. The goal of this study is to identify the gene for BCD.Methods: The BCD region was refined by linkage analysis and haplotype analysis in 10 BCD families. A YAC/BAC/PAC contig was constructed in BCD region for physical map. Candidate genes in this region were screened for mutation by direct sequencing of PCR amplified exons from BCD patients. Gene expression was tested by PCR of cDNA from human multiple tissues. The protein structure and mutation effects of CYP4V2 were predicted by homology modeling. Results:The BCD region on 4q35 was refined to an interval flanked centromerically by D4S2924. Candidate genes identified by physical mapping and screening the NCBI and Celera human genomic sequence databases were sequenced for sequence changes. Mutations in the novel gene CYP4V2 were found in 13 of 14 familial and 11 of 12 sporadic BCD patients and were absent from 50 controls. Molecular modeling analysis of CYP4V2 predicts that most of these mutations should result in a loss of enzymatic function. CYP4V2 is widely expressed in human tissues and its structure predicts that it might have a role in fatty acid and/or steroid metabolism, consistent with previous biochemical studies of BCD patients.Conclusions: We mapped BCD to chromosome 4q35.1 and identified mutations of the novel gene CYP4V2 in 24 of 26 unrelated BCD patients. CYP4V2 shows structural similarities to cytochrome P450 family members active in fatty acid or steroid metabolism.

Keywords: retinal degenerations: hereditary • gene screening • mutations