TRANSMISSION OF 2 NOVEL MUTATIONS IN A PEDIGREE WITH FAMILIAL LECITHIN-CHOLESTEROL ACYLTRANSFERASE DEFICIENCY - STRUCTURE-FUNCTION-RELATIONSHIPS AND STUDIES IN A COMPOUND HETEROZYGOUS PROBAND

Two novel mutations were identified in a compound heterozygous male wi th lecithin:cholesterol acyltransferase (LCAT) deficiency. Exon sequen ce determination of the LCAT gene of the proband revealed two novel he terozygous mutations in exons one (C110T) and six (C991T) that predict non-conservative amino add substitutions (Thr13Met and Pro307Ser, res pectively). To assess the distinct functional impact of the separate m utant alleles, studies were conducted in the proband's 3-generation pe digree, The compound heterozygous proband had negligible HDL and sever ely reduced apolipoprotein A-I, LCAT mass, LCAT activity, and choleste rol esterification rate (CER), The proband's mother and tao sisters we re heterozygous for the Pro307Ser mutation and had low HDL, markedly r educed LCAT activity and CER, and the propensity for significant reduc tions in LCAT protein mass, The proband's father and two daughters wer e heterozygous for the Thr13Met mutation and also displayed low HDL, r educed LCAT activity and CER, and more modest decrements in LCAT mass. Mean LCAT specific activity was severely impaired in the compound het erozygous proband and was reduced by 50% in individuals heterozygous f or either mutation, compared to wild type family members. It is also s hown that the two mutations impair both catalytic activity and express ion of the circulating protein.