TY - JOUR
T1 - Molecular basis of fish-eye disease in a patient from Spain
T2 - Characterization of a novel mutation in the LCAT gene and lipid analysis of the cornea
AU - Blanco-Vaca, Francisco
AU - Qu, Shi Jing
AU - Fiol, Concha
AU - Fan, Hui Zhen
AU - Pao, Quein
AU - Marzal-Casacuberta, Africa
AU - Albers, John J.
AU - Hurtado, Isabel
AU - Gracia, Vicente
AU - Pintó, Xavier
AU - Martí, Tomás
AU - Pownall, Henry J.
N1 - Copyright:
Copyright 2017 Elsevier B.V., All rights reserved.
PY - 1997
Y1 - 1997
N2 - 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 Arg 99→Cys substitution. Secretion of LCAT (Arg 99→Cys) 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 (Arg 99→Cys) 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.
AB - 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 Arg 99→Cys substitution. Secretion of LCAT (Arg 99→Cys) 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 (Arg 99→Cys) 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.
KW - Arteriosclerosis
KW - Cholesteryl esters
KW - Corneal opacities
KW - HDL
KW - Lecithin Acyltransferase deficiency
KW - Lipoproteins
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U2 - 10.1161/01.ATV.17.7.1382
DO - 10.1161/01.ATV.17.7.1382
M3 - Article
C2 - 9261271
AN - SCOPUS:16944364616
VL - 17
SP - 1382
EP - 1391
JO - Arteriosclerosis, Thrombosis, and Vascular Biology
JF - Arteriosclerosis, Thrombosis, and Vascular Biology
SN - 1079-5642
IS - 7
ER -