A normal rate of cellular cholesterol removal can be mediated by plasma from a patient with familial lecithin-cholesterol acyltransferase (LCAT) deficiency.

Abstract Lecithin–cholesterol acyltransferase (LCAT) is the major enzyme involved in the esterification of cholesterol in circulating plasma lipoproteins. In the present study, we describe the molecular defects in the LCAT gene and in lipoprotein metabolism of a 34-year-old patient presenting with features of classic familial LCAT deficiency. DNA sequencing revealed two separate point mutations in exon 3 of the patient's LCAT gene: a C to A substitution converting Tyr 83 to a Stop and a C to T transition converting an Arg 99 to a Cys. Digestion of patient PCR-amplified DNA with the restriction enzymes Acc I and Aci I established that the patient was a compound heterozygote for both mutations. In vitro expression of LCAT (Arg 99 →Cys) in human embryonic kidney-293 cells demonstrated reduced expression, as well as reduced secretion and/or increased intracellular degradation of the mutant enzyme with significantly decreased α-LCAT specific activity, thus, establishing the functional significance of the LCAT (Arg 99 →Cys) mutation. The plasma cholesterol esterification rate (CER, 2±0.3 nmol/ml/h), α-LCAT activity (2.9±0.1 nmol/ml/h) and LCAT concentration (0.3±0.1 μg/ml) were 2.9%, 2.3% and 6.1% that of normal subjects, respectively. Analysis of the patient's plasma lipid profile revealed reduced plasma concentrations of total cholesterol (111±0.5 mg/dl), HDL cholesterol (1.6±0.2 mg/dl), apolipoprotein (apo) A-I (52±4 mg/dl) and apo A-II (11±0.5 mg/dl). Nevertheless, for the first time, we demonstrate that the LCAT-deficient plasma is as efficient as control plasma in cholesterol efflux experiments performed with [ 3 H]-cholesterol loaded fibroblasts. This result could explain the absence of premature atherosclerosis in this LCAT-deficient patient.