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

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^a, Alicia Jenkins^a, Richard L. Klein^a, Timothy Lyons^a, Brett Wagenhorst^b, Jonny St. Armand^c, Santica M. Marcovina^d, John J. Albers^d, P. Haydn Pritchard^c, and W. Timothy Garvey^a
^a Division of Endocrinology, Department of Medicine, Medical University of South Carolina, and Ralph H. Johnson Veterans Affairs Medical Center, Charleston, SC 29425
^b Eye Clinic, 29th Medical Group, Shaw Air Force Base, SC 29152
^c Atherosclerosis Specialty Laboratory, Department of Pathology and Laboratory Medicine, St. Paul's Hospital, University of British Columbia, Vancouver, BC, Canada, V6Z 1Y6
^d Northwest Lipid Research Laboratories, University of Washington, Seattle, WA 98103

Correspondence to: George Argyropoulos.

Two novel mutations were identified in a compound heterozygousmale with lecithin:cholesterol acyltransferase (LCAT) deficiency.Exon sequence determination of the LCAT gene of the probandrevealed 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 distinctfunctional impact of the separate mutant alleles, studies wereconducted in the proband's 3-generation pedigree. The compoundheterozygous proband had negligible HDL and severely reducedapolipoprotein A-I, LCAT mass, LCAT activity, and cholesterolesterification rate (CER). The proband's mother and two sisterswere heterozygous for the Pro307Ser mutation and had low HDL,markedly reduced LCAT activity and CER, and the propensity forsignificant reductions in LCAT protein mass. The proband's fatherand two daughters were heterozygous for the Thr13Met mutationand also displayed low HDL, reduced LCAT activity and CER, andmore modest decrements in LCAT mass. Mean LCAT specific activitywas severely impaired in the compound heterozygous proband andwas reduced by 50% in individuals heterozygous for either mutation,compared to wild type family members. It is also shown thatthe two mutations impair both catalytic activity and expressionof 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. Transmissionof two novel mutations in a pedigree with familial lecithin:cholesterolacyltransferase deficiency: structure–function relationshipsand studies in a compound heterozygous proband. J. Lipid Res.1998. 39: 1870–1876.

Supplementary key words: high density lipoprotein, LCAT activity, polymerase chain reaction,lipoprotein [a], substrate recognition binding site, familialLCAT deficiency, fish- eye disease

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Original Article

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