Anren Li, Xiaodong Jiao, Francis L. Munier, Daniel F

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Bietti Crystalline Corneoretinal Dystrophy Is Caused by Mutations in the Novel Gene CYP4V2 Anren Li, Xiaodong Jiao, Francis L. Munier, Daniel F. Schorderet, Wenliang Yao, Fumino Iwata, Mutsuko Hayakawa, Atsushi Kanai, Muh Shy Chen, Richard Alan Lewis, John Heckenlively, Richard G. Weleber, Elias I. Traboulsi, Qingjiong Zhang, Xueshan Xiao, Muriel Kaiser-Kupfer, Yuri V. Sergeev, J. Fielding Hejtmancik The American Journal of Human Genetics Volume 74, Issue 5, Pages 817-826 (May 2004) DOI: 10.1086/383228 Copyright © 2004 The American Society of Human Genetics Terms and Conditions

Figure 1 Pedigrees of selected families with BCD with haplotypes of markers in the BCD region. Family 33001 was used in the genomewide scan. Recombinants in individual 4 of family 33010 and individual 6 of family 33011 set the centromeric boundary at D4S2924, as does the lack of homozygosity in D4S3047, D4S3032, and D4S2924 in individual 3 of consanguineous family 33005. The American Journal of Human Genetics 2004 74, 817-826DOI: (10.1086/383228) Copyright © 2004 The American Society of Human Genetics Terms and Conditions

Figure 2 A, Physical map of BCD region at 4q35.1. The BCD region is covered contiguously by 6 overlapping YACs and 32 BACs, representing the shortest path. The STS marker positions are from the NCBI database. B, CYP4V2 cDNAs. Five overlapping cDNA fragments obtained by direct PCR and 5′ and 3′ RACE from human retinal cDNA and RPE cDNA provide a 2,041-bp cDNA. Sequence homology searches show partial sequence overlap with three NCBI predicted cDNA sequences: XM209611, XM114391, and XM209612. C, CYP4V2 gene structure. CYP4V2 gene structure is assembled by alignment of the cDNA sequence to genomic DNA sequence. The 11 identified exons are flanked by recognizable splice sites. The coding region extends as one ORF from the first Met (ATG) codon in exon 1 to the stop (TAA) codon in exon 11. This novel gene consists of 11 exons and spans 19 kb. Thirteen mutations of the CYP4V2 gene found in 23 of 25 unrelated patients with BCD are indicated below the gene structure. The American Journal of Human Genetics 2004 74, 817-826DOI: (10.1086/383228) Copyright © 2004 The American Society of Human Genetics Terms and Conditions

Figure 3 Structure of CYP4V2 protein and selected mutations. A, CYP4V2 protein structure. α Helices are shown as red cylinders, β sheets are shown as yellow ribbons, and the porphyrin ring is shown in blue. B, The peptide preserved by G134X, which truncates the protein just within the main globular domain, is shown in red, and truncated sequences are shown in blue, with the exception of exon 7, which is shown in green. C, The 15-bp deletion, including the 3′ (acceptor) splice site for exon 7, which removes the G, H, and part of the central I helices (green) and their connecting loops and causes uncoiling and displacement of the central I helix (the normal position is shown in light blue, and the displaced position is shown in dark blue). D, Replacement of hydrophobic aromatic tryptophan near or in the transmembrane segment with positively charged arginine (W44R). E, R508H, which might influence heme coordination. F, H331P, predicted to disrupt the I helix. G, I111T, near the surface of the molecule. H, S341P, predicted to disrupt the I helix. The American Journal of Human Genetics 2004 74, 817-826DOI: (10.1086/383228) Copyright © 2004 The American Society of Human Genetics Terms and Conditions

Figure 4 Expression pattern of CYP4V2. PCR was performed with cDNA from various tissues, using primers from exons 5 and 11. The lymphocyte (“ptnt”) sample is from patient 4 in family 33002 and displays a 727-bp fragment lacking exon 7. The negative control is H2O, and the positive control is pooled cDNA from human tissues (Universal cDNA pool [Clontech]). The American Journal of Human Genetics 2004 74, 817-826DOI: (10.1086/383228) Copyright © 2004 The American Society of Human Genetics Terms and Conditions

Figure B1 Alignment of CYP4V2 with CYP450 family members. Mus musculus CYP4V3 shows the highest identify, whereas rabbit CYP2C5 and Bacillus mesenterium CYPBM3, whose structures have been determined crystallographically, are further removed. CYPBM3 was used to model the high-homology area surrounding the active site, and CYP2C5 was used to model the amino-terminal regions for which homology to CYPBM3 was low. The American Journal of Human Genetics 2004 74, 817-826DOI: (10.1086/383228) Copyright © 2004 The American Society of Human Genetics Terms and Conditions