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(Arteriosclerosis, Thrombosis, and Vascular Biology. 1997;17:1382-1391.)
© 1997 American Heart Association, Inc.

Articles

Molecular Basis of Fish-Eye Disease in a Patient From Spain

Characterization of a Novel Mutation in the LCAT Gene and Lipid Analysis of the Cornea

Francisco Blanco-Vaca; Shi-Jing Qu; Concha Fiol; Hui-Zhen Fan; Quein Pao; Àfrica Marzal-Casacuberta; John J. Albers; Isabel Hurtado; Vicente Gracia; Xavier Pintó; Tomás Martí; ; Henry J. Pownall

From the Department of Medicine, Baylor College of Medicine and Methodist Hospital, Houston, Tex (F.B.-V., S.-J.Q., H.-Z.F., Q.P., H.J.P.); Servei de Bioquímica and Institut de Recerca, Hospital de la Santa Creu I Sant Pau, and Departament de Bioquímica I Biologia Molecular, Universitat Autònoma de Barcelona, Spain (F.B.-V., À.M.-C.); Serveis d'Oftalmologia, Medicina Interna i Recerca Experimental, Residencia Sanitària i Universitària Prínceps d'Espanya, L'Hospitalet de Llobregat, Barcelona, Spain (C.F., I.H., V.G., X.P., T.M.); and Department of Medicine, Northwest Lipid Research Laboratories, University of Washington, Seattle (J.J.A.). The first two authors contributed equally to this study.

Correspondence to Henry J. Pownall, Baylor College of Medicine and Methodist Hospital, Department of Medicine, 6565 Fannin MS A601, Houston, TX 77030. E-mail hpownall{at}bcm.tmc.edu

Abstract The genetic and biochemical basis of fish-eye disease (FED) was investigated in a 63-year-old female proband with low plasma HDL cholesterol. Analyses of corneal and plasma lipids of the proband were consistent with impaired lecithin:cholesterol acyltransferase (LCAT) activity. Free cholesterol and phospholipid levels were elevated relative to control values, whereas cholesteryl ester levels were greatly reduced. Fatty acid compositions of corneal lipids from the proband and control subjects differ from the respective fatty acid compositions of their plasma lipids. This suggests that the metabolic pathways and acyl chain specificities for phospholipid, cholesteryl ester, and triglyceride metabolism within the cornea are distinct from those of plasma. Sequencing of the LCAT gene from the proband revealed a novel mutation at nucleotide 399, corresponding to an Arg₉₉Cys substitution. Secretion of LCAT (Arg₉₉Cys) by transfected COS-6 cells was 50% of that of the wild type, but its specific activity against reassembled HDL was 93% lower than that of wild-type LCAT. The specific activities of wild-type and LCAT (Arg₉₉Cys) against LDL were reduced similarly, suggesting that the appearance of the FED phenotype does not require enhanced activity against LDL. Our data support the hypothesis that FED is a partial LCAT deficiency in which poor esterification in specific types of HDL particles may contribute to the appearance of the corneal opacities.

Key Words: lipoproteins • HDL • lecithin acyltransferase deficiency • cholesteryl esters • corneal opacities • arteriosclerosis

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