lele frequency, 0.84). The OR for DVT per risk allele was 1.24 (95% confidence interval [95%CI], 1.11-1.37) for rs13146272, 1.29 (95% CI, 1.10-1.49) for rs2227589, and 1.15 (95% CI, 1.01-1.30) for rs1613662. In the region of CYP4V2, we identified 4 additional SNPs (in CYP4V2, KLKB1, and F11) that were also associated with both DVT (highest OR per risk allele, 1.39; 95% CI, 1.11-1.74) and coagulation factor XI level (highest increase per risk allele, 8%; 95% CI, 5%-11%). Conclusions We identified SNPs in several genes that were associated with DVT. We also found SNPs in the region around the SNP in CYP4V2 (rs13146272) that were associated with both DVT and factor XI levels. These results show that common genetic variation plays an important role in determining thrombotic risk.

/pdf/gene-variants-associated-with-deep-vein-thrombosis-171e8rvrep.pdf

Gene Variants Associated With Deep Vein Thrombosis

Bietti crystalline corneoretinal dystrophy (BCD) is an autosomal recessive retinal dystrophy characterized by multiple glistening intraretinal crystals scattered over the fundus, a characteristic degeneration of the retina, and sclerosis of the choroidal vessels, ultimately resulting in progressive night blindness and constriction of the visual field. The BCD region of chromosome 4q35.1 was refined to an interval flanked centromerically by D4S2924 by linkage and haplotype analysis; mutations were found in the novel CYP450 family member CYP4V2 in 23 of 25 unrelated patients with BCD tested. The CYP4V2 gene, transcribed from 11 exons spanning 19 kb, is expressed widely. Homology to other CYP450 proteins suggests that CYP4V2 may have a role in fatty acid and steroid metabolism, consistent with biochemical studies of patients with BCD.

https://www.cell.com/ajhg/pdf/S0002-9297(07)64351-1.pdf

Bietti crystalline corneoretinal dystrophy is caused by mutations in the novel gene CYP4V2.

Ligand Specificity of Brain Lipid-binding Protein

Familial exudative vitreoretinopathy (FEVR) is a hereditary eye disorder that affects both the retina and vitreous body. Autosomal recessive FEVR was diagnosed in multiple individuals from three consanguineous families of European descent. A candidate-locus–directed genome scan shows linkage to the region on chromosome 11q flanked by markers D11S905 and D11S1314. The maximum LOD score of 3.6 at θ=0 is obtained with marker D11S987. Haplotype analysis confirms that the critical region is the 22-cM (311-Mb) interval flanked by markers D11S905 and D11S1314. This region contains LRP5 but not FZD4; mutations in both of these genes cause autosomal dominant FEVR. Sequencing of LRP5 shows, in all three families, homozygous mutations R570Q, R752G, and E1367K. This suggests that mutations in this gene can cause autosomal recessive as well as autosomal dominant FEVR.

Autosomal Recessive Familial Exudative Vitreoretinopathy Is Associated with Mutations in LRP5

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

(WD). RESULTS. Pulse‐ chase experiments with labeled fatty acids in all groups showed that, after 1 hour, radioactivity was largely confined to the triacylglyceride (TG) and choline phosphoglyceride (CPG) pools. However, after several hours, radioactivity was transferred from the TG and CPG pools, some going to the serine and ethanolamine phosphoglyceride (SPG and EPG) pools. Fibroblasts from all groups showed direct transfer of fatty acids (FAs) into CPG and EPG. Incorporation of labeled FAs into the EPG pool paralleled extensive desaturation and elongation of 18:2n-6 to 22:5n-6 and 18:3n-3 to 22:6n-3. Fibroblasts from patients with WD (a lysosomal acid lipase deficiency characterized by excessive lipid accumulation), showed higher incorporation of 18:2n-6 into TGs than did normal or BCD fibroblasts. Conversely, fibroblasts from patients with BCD showed lower conversion of 18:3n-3, but not of 18:2n-6, into polyunsaturated FAs (PUFAs) than those of normal subjects or patients with WD. This was true for total FAs, CPGs, and EPGs. Similar results were found in both fibroblasts and lymphocytes; however, unlike fibroblasts, lymphocytes from normal subjects showed similar levels of incorporation of FAs into EPGs and CPGs. In contrast, incorporation of 18:3n-3 into EPGs was decreased in lymphocytes from patients with BCD. CONCLUSIONS. BCD is characterized by a lower than normal conversion of FA precursors into n-3 PUFA, whereas there is a higher than normal level of n-6 and n-3 FAs incorporation into TGs in cells from patients with WD. These findings raise the possibility that abnormal lipid metabolism associated with BCD is the result of deficient lipid binding, elongation, or desaturation in contrast to the lysosomal acid lipase deficiency found in Wolman disease. (Invest Ophthalmol Vis Sci. 2001;42: 1707‐1714)

The metabolism of fatty acids in human Bietti crystalline dystrophy.

Bietti crystalline corneoretinal dystrophy (BCD) is an autosomal recessive retinal degeneration characterized by multiple glistening intraretinal dots scattered over the fundus, degeneration of the retina, and sclerosis of the choroidal vessels, ultimately resulting in progressive night blindness and constriction of the visual field. Although BCD has been associated with abnormalities in fatty-acid metabolism and absence of fatty-acid binding by two cytosolic proteins, the genetic basis of BCD is unknown. We report linkage of the BCD locus to D4S426 (maximum LOD score [Zmax] 4.81; recombination fraction [θ] 0), D4S2688 (Zmax=3.97; θ=0), and D4S2299 (Zmax=5.31; θ=0), on chromosome 4q35-4qtel. Multipoint analysis confirmed linkage to the region telomeric of D4S1652 with a Zmax of 5.3 located 4 cM telomeric of marker D4S2930.

Genetic linkage of Bietti crystallin corneoretinal dystrophy to chromosome 4q35

Identification, isolation, and characterization of a 32-kDa fatty acid-binding protein missing from lymphocytes in humans with Bietti crystalline dystrophy (BCD).

Purpose. To determine if soluble binding proteins (BP) for fatty acids (FA), particularly docosahexaenoic acid (DHA), could be identified in the cytosol of rat and bovine retinas under in vitro and in vivo conditions. Methods. In vitro, cytosol fractions from normal bovine and rat retinas were delipidated and incubated with [ 14 C]-DHA with or without a number of competing fatty acids. After crosslinking bound FA to BP, the proteins were separated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and radioactivity determined in each fraction. For in vivo experiments, rats received [ 14 C]-DHA by gavage. At selected periods after ingestion, retinas were collected and cytosolic fractions were prepared from each. These were crosslinked and subjected to SDS-PAGE, and radioactivity was determined in each fraction. Results. In vitro, several peaks of radioactivity (approximately 13, 20, 32, 43-45, 50, 63, and 94-105 kd) were found that exhibited [ 14 C]-DHA binding. Relative specificity of binding was assessed by blocking of the [ 14 C]-DHA binding with unlabeled DHA and by competition experiments with other FAs. After in vivo ingestion of [ 14 C]-DHA, a large peak of radioactivity was observed at 43 kd by 4 hours. At 6 hours, this peak decreased and, after 24 hours, it approached baseline. Conclusions. These findings demonstrate that there is a discrete grouping of proteins in retinal cytosol capable of binding DHA and other FA. Although the identities of these proteins have yet to be determined, the group may include a member of the 12- to 15-kd group of small fatty acid binding proteins (FABP). In particular, a unique 43-kd binding peak could play a major role in the uptake, binding, or both of DHA by the retina in vivo. Invest Ophthalmol Vis Sci. 1995 ;36 :2032-2039.

June Lee

Papers

The metabolism of fatty acids in human Bietti crystalline dystrophy.

Genetic linkage of Bietti crystallin corneoretinal dystrophy to chromosome 4q35

Identification, isolation, and characterization of a 32-kDa fatty acid-binding protein missing from lymphocytes in humans with Bietti crystalline dystrophy (BCD).

Soluble-binding proteins for docosahexaenoic acid are present in neural retina.