Transmission of two novel mutations in a pedigree with familial lecithin:cholesterol acyltransferase deficiency: structure–function relationships and studies in a compound heterozygous proband

George Argyropoulos,Alicia Jenkins,Richard L Klein,Timothy Lyons,Brett Wagenhorst,Jonny St Armand,Santica M Marcovina,John J Albers,P Haydn Pritchard,W Timothy Garvey

doi:10.1016/s0022-2275(20)32175-1

Abstract

Two novel mutations were identified in a compound heterozygous male with lecithin:cholesterol acyltransferase (LCAT) deficiency. Exon sequence determination of the LCAT gene of the proband revealed two novel heterozygous mutations in exons one (C110T) and six (C991T) that predict non-conservative amino acid substitutions (Thr13Met and Pro307Ser, respectively). To assess the distinct functional impact of the separate mutant alleles, studies were conducted in the proband's 3-generation pedigree. The compound heterozygous proband had negligible HDL and severely reduced apolipoprotein A-I, LCAT mass, LCAT activity, and cholesterol esterification rate (CER). The proband's mother and two sisters were heterozygous for the Pro307Ser mutation and had low HDL, markedly reduced LCAT activity and CER, and the propensity for significant reductions in LCAT protein mass. The proband's father and two daughters were heterozygous for the Thr13Met mutation and also displayed low HDL, reduced LCAT activity and CER, and more modest decrements in LCAT mass. Mean LCAT specific activity was severely impaired in the compound heterozygous proband and was reduced by 50% in individuals heterozygous for either mutation, compared to wild type family members. It is also shown that the two mutations impair both catalytic activity and expression of the circulating protein.—Argyropoulos, G., A. Jenkins, R. L. Klein, T. Lyons, B. Wagenhorst, J. St. Armand, S. M. Marcovina, J. J. Albers, P. H. Pritchard, and W. T. Garvey. Transmission of two novel mutations in a pedigree with familial lecithin:cholesterol acyltransferase deficiency: structure–function relationships and studies in a compound heterozygous proband.

Highlights

Two novel mutations were identified in a compound heterozygous male with lecithin:cholesterol acyltransferase (LCAT) deficiency
Members of the immediate family of the proband participated in the study and circulating lipids, lipoproteins, LCAT activity, LCAT mass, and cholesterol esterification rate were measured in all participating individuals (Table 1)
The serum apolipoprotein A-I level of the proband was less than 50% of the minimum of the reference range (Table 1) and was depressed, albeit less dramatically, in the father, mother, sister 2, and daughter 1 (Table 1)

Summary

Introduction

Two novel mutations were identified in a compound heterozygous male with lecithin:cholesterol acyltransferase (LCAT) deficiency. The compound heterozygous proband had negligible HDL and severely reduced apolipoprotein A-I, LCAT mass, LCAT activity, and cholesterol esterification rate (CER). The proband’s mother and two sisters were heterozygous for the Pro307Ser mutation and had low HDL, markedly reduced LCAT activity and CER, and the propensity for significant reductions in LCAT protein mass. Transmission of two novel mutations in a pedigree with familial lecithin:cholesterol acyltransferase deficiency: structure–function relationships and studies in a compound heterozygous proband. Depending on the measured LCAT activity, LCAT mass, HDL concentrations, and clinical characteristics, mutations in the human LCAT gene have been described and classified [15] as familial LCAT deficiency (FLD) or as fish-eye disease (FED)

Methods

Results

Conclusion