title: A unique genetic and biochemical presentation of fish-eye disease.
abstract: This paper describes a novel genetic defect which causes fish-eye disease in four homozygous probands and its biochemical presentation in 34 heterozygous siblings. The male index patient presented with premature coronary artery disease, corneal opacification, HDL deficiency, and a near total loss of plasma lecithin:cholesterol acyltransferase (LCAT) activity. Sequencing of the LCAT gene revealed homozygosity for a novel missense mutation resulting in an Asp131 - Asn (N131D) substitution. Heterozygotes showed a highly significant reduction of HDL-cholesterol and apolipoprotein A-I levels as compared with controls which was associated with a specific decrease of LpA-I:A-II particles. Functional assessment of this mutation revealed loss of specific activity of recombinant LCAT(N131D) against proteoliposomes. Unlike other mutations causing fish-eye disease, recombinant LCAT(N131D) also showed a 75% reduction in specific activity against LDL. These unique biochemical characteristics reveal the heterogeneity of phenotypic expression of LCAT gene defects within a range specified by complete loss of LCAT activity and the specific loss of activity against HDL. The impact of this mutation on HDL levels and HDL subclass distribution may be related to the premature coronary artery disease observed in the male probands.
authors.affiliation: Department of Haemostasis, Thrombosis, Atherosclerosis and Inflammation Research, Academic Medical Centre, University of Amsterdam, The Netherlands.
authors.forename: J A
authors.initials: JA
authors.lastname: Kuivenhoven
authors.forename: E J
authors.initials: EJ
authors.lastname: van Voorst tot Voorst
authors.forename: H
authors.initials: H
authors.lastname: Wiebusch
authors.forename: S M
authors.initials: SM
authors.lastname: Marcovina
authors.forename: H
authors.initials: H
authors.lastname: Funke
authors.forename: G
authors.initials: G
authors.lastname: Assmann
authors.forename: P H
authors.initials: PH
authors.lastname: Pritchard
authors.forename: J J
authors.initials: JJ
authors.lastname: Kastelein
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000595:Amino Acid Sequence; D016632:Apolipoprotein A-I / Q000097:blood; D001216:Asparagine; D001224:Aspartic Acid; D001483:Base Sequence; D008076:Cholesterol, HDL / Q000097:blood; D017931:DNA Primers; D006580:Genetic Carrier Screening; D006720:Homozygote; D006801:Humans; D007863:Lecithin Cholesterol Acyltransferase Deficiency / Q000235:genetics*; D017270:Lipoprotein(a) / Q000031:analogs & derivatives / Q000097:blood; D008075:Lipoproteins, HDL / Q000097:blood / Q000172:deficiency / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D010375:Pedigree; D010641:Phenotype; D007862:Phosphatidylcholine-Sterol O-Acyltransferase / Q000097:blood / Q000235:genetics*; D017354:Point Mutation; D016133:Polymerase Chain Reaction; D012016:Reference Values; D015183:Restriction Mapping
chemical_list: D016632:Apolipoprotein A-I; D008076:Cholesterol, HDL; D017931:DNA Primers; D017270:Lipoprotein(a); D008075:Lipoproteins, HDL; D001224:Aspartic Acid; C078260:lipoprotein A-I; D001216:Asparagine; D007862:Phosphatidylcholine-Sterol O-Acyltransferase